JP2019516687A - Indoleamine 2,3-dioxygenase inhibitors and methods of use thereof - Google Patents

Abstract

Compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing the compounds and proliferative disorders such as cancer using the compounds of the present invention, viral infections and / or Disclosed are methods of treating inflammatory disorders.

Description

This application claims the benefit of US Provisional Application 62 / 331,871, filed May 4, 2016, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates generally to compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing the compounds and proliferative properties such as cancer using the compounds of the present invention The invention relates to a method of treating disorders, viral infections and / or autoimmune diseases.

BACKGROUND OF THE INVENTION Indoleamine 2,3-dioxygenase (IDO; also known as IDO1) is an IFN-γ target gene that has a role in immunomodulation. IDO is an oxidoreductase, one of two enzymes that catalyzes the first and rate-limiting step from tryptophan to N-formyl-kynurenine. It exists as a 41 kD monomer found in several cell populations including immune cells, endothelial cells and fibroblasts. IDO is relatively well conserved among species and shares 63% sequence identity at the amino acid level between mouse and human. The crystal structure and data from site directed mutagenesis indicate that both substrate binding and the relationship between substrate and iron binding dioxygenase are required for activity. A homolog of IDO (IDO2) has been identified and shares 44% amino acid sequence homology with IDO, but its function differs significantly from that of IDO. (For example, Serafini, P. et al., Semin. Cancer Biol., 16 (1): 53-65 (Feb. 2006) and Ball, HJ et al., Gene, 396 (1): 203-213 (Jul 1, 2007)).

  IDO plays a major role in immune regulation, and its immunosuppressive function is revealed in several ways. Importantly, IDO regulates immunity at the T cell level, and there is a certain relationship between IDO and cytokine production. Furthermore, tumors often manipulate immune function by upregulating IDO. Therefore, modulation of IDO can have therapeutic impact on a number of diseases, disorders and conditions.

  There is a pathophysiological link between IDO and cancer. Disruption of immune homeostasis is closely associated with tumor growth and progression, and production of IDO in the tumor microenvironment appears to help with tumor growth and metastasis. Furthermore, increased levels of IDO activity are associated with a wide variety of tumors (Brandacher, G. et al., Clin. Cancer Res., 12 (4): 1144-1151 (Feb. 15, 2006)). .

  Cancer treatment generally requires chemotherapy and radiation therapy after surgical resection. Standard treatment regimens have shown that recovery of primary tumor growth, and often more importantly, the ability of tumor cells to escape by dissemination to distant metastases, can alter the degree of long-term success to a high degree. Recent advances in the treatment of cancer and cancer related diseases, disorders and conditions include the use of combination therapy, which combines immunotherapy with more classical chemotherapy and radiation therapy. In most scenarios, immunotherapy is less toxic than classical chemotherapy because it utilizes the patient's own immune system to identify and eliminate tumor cells.

  In addition to cancer, IDO is associated with immunosuppression, chronic infections and autoimmune diseases or disorders (eg, rheumatoid arthritis), among other conditions. Therefore, suppression of tryptophan degradation by IDO activity inhibition has extremely great therapeutic value. In addition, IDO inhibitors can be used to enhance T cell activation when T cells are suppressed by pregnancy, malignancy or virus (eg, HIV). Although their role is not well understood, IDO inhibitors may also be useful in the treatment of patients with neurological or neuropsychiatric diseases or disorders (eg, depression).

  Small molecule inhibitors of IDO are being developed for the treatment or prevention of IDO related diseases. For example, IDO inhibitors 1-methyl-DL-tryptophan; p- (3-benzofuranyl) -DL-alanine; p- [3-benzo (b) thienyl] -DL-alanine; and 6-nitro-L- Tryptophan has been used to modulate T cell mediated immunity by modification of local extracellular concentrations of tryptophan and tryptophan metabolites (WO 99/29310). Compounds having IDO inhibitory activity are further reported in PCT Publication WO 2004/094409.

  In view of the role indoleamine 2,3-dioxygenase has in a wide range of diseases, disorders and conditions and the limitations (eg, efficacy) of current IDO inhibitors, novel IDO modulators and related compositions and methods is necessary.

SUMMARY OF THE INVENTION The present invention relates to Formula I and Formula II
In which X is CH or N; T is CH or N; R ¹ is H, halo or C ₁ -C ₆ haloalkyl; R ^1A is H, halo or C ₁ -C ₆ haloalkyl Y is CH or N; n is 0, 1, 2, 3 or 4; W is N or CR ⁴ where R ⁴ is H or C (C ₁ -C ₆ alkyl) in it, one V is independently selected from _C 1 -C ₆ alkyl and _C 3 -C ₆ cycloalkyl optionally, two or three or _C 1 -C be substituted with a substituent ₆ R ² is H or C ₁ -C ₆ alkyl; Z is a bond or ₁ independently selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl And may be substituted by 2 or 3 substituents C ₁ -C ₆ alkylene; B is optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN , Aryl optionally substituted with one, two or three R substituents independently selected from aryl or -O aryl; or B is optionally -OH, C ₁ -C ₆ alkyl 1, 2, or 3 independently selected from C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN, aryl or -O aryl may be substituted with R substituent _C is 3 _{-C 12} cycloalkyl. ]
The compound of

  Also within the scope of the invention are pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of the compounds of Formula I and Formula II.

  The invention also relates to a pharmaceutical composition comprising one or more compounds of formula I and / or formula II. The invention also relates to a method of treating cancer using one or more compounds of formula I and / or formula II.

Detailed Description of the Invention Compounds of the Invention
The compound of

  According to the invention, X is CH or N. In one aspect, X is CH. In another embodiment, X is N.

  According to the invention, T is CH or N. In one aspect, T is CH. In another embodiment, T is N.

  In certain embodiments of formula I, X is CH and T is CH. In another embodiment, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N.

According to the invention, R ¹ is H, halo or C ₁ -C ₆ haloalkyl. In another embodiment, R ¹ is H, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In certain embodiments, R ¹ is H. In certain embodiments, R ¹ is halo (F, Cl, Br or I), preferably F. In another embodiment, R ¹ is C ₁ -C ₆ alkyl, such as methyl, ethyl, isopropyl, butyl or t-butyl. In still other embodiments, R ¹ is C ₁ -C ₆ haloalkyl, eg, —CF ₃ . In certain embodiments, R ¹ is halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In another embodiment, R ¹ is halo or C ₁ -C ₆ haloalkyl.

In those aspects of the invention involving compounds of formula I, when R ¹ is halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, R ¹ is preferably present at the 4-position carbon of the ring . In other embodiments of the invention that include compounds of Formula I, when R ¹ is halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, R ¹ can be present at the 2-position carbon of the ring. Preferably, in these embodiments of the invention comprising a compound of formula I, R ¹ is F or CF ₃ of ring 4 carbon.

In those aspects of the invention involving compounds of formula II, when R ¹ is halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, R ¹ is preferably present at the 2 carbon positions of the ring . In other embodiments of the invention that include compounds of Formula II, when R ¹ is halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, R ¹ can be at the 3 carbon position of the ring. Preferably, in those embodiments of the invention involving compounds of Formula II, when R ¹ is F or CF ₃ at ring 2 carbon.

According to the invention, R ^1A is H, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. In a preferred embodiment, R ^1A is H. In certain embodiments, R ^1A is halo (F, Cl, Br or I). In another preferred embodiment, R ^1A is C ₁ -C ₆ alkyl, such as methyl, ethyl, isopropyl, butyl or t-butyl. In still other embodiments, R ^1A is C ₁ -C ₆ haloalkyl, eg, —CF ₃ .

According to the invention, Y is CH or N. In one aspect, Y is CH. In another embodiment, Y is N. In another embodiment, Y is -C _(C 1 -C ₆ alkyl), for example, a -C (CH ₃₎ or -C _(CH 2 _{CH 3).}

  According to the invention, n is 0, 1, 2, 3 or 4. In a preferred embodiment, n is 2. In another aspect n is 0. In another embodiment n is 1. In yet another embodiment, n is 3. In yet another embodiment, n is 4. In certain embodiments, n is 0-2 or 1-2. In still other embodiments, n is 1-3.

According to the invention, W is N or CR ⁴ , wherein R ⁴ is H or-(C ₁ -C ₆ alkyl)-. In one aspect, W is N. In another embodiment, W is CR ⁴ and R ⁴ is H, eg, W is -CH-. In certain embodiments, W is CR ⁴ and R ⁴ is-(C ₁ -C ₆ alkyl), methyl, methyl, propyl, isopropyl, butyl, s-butyl, t-butyl and the like (ie, W is- C (C ₁ -C ₆ alkyl)-).

In one aspect, Y is CH and W is CH. In another embodiment, Y is CH and W is N. In another embodiment, Y is N and W is CH. In still other embodiments, Y is N and W is N. In certain embodiments, Y is CH and W is C (C ₁ -C ₆ alkyl). In another embodiment, Y is N and W is C (C ₁ -C ₆ alkyl).

According to the invention, V is unsubstituted C ₁ -C ₆ alkylene, for example unsubstituted C ₁ -C ₅ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₃ alkylene, C ₁ -C ₂ alkylene or C ₁ It is alkylene. In another aspect of the invention, V is independently selected from C ₁ -C ₆ alkyl (eg methyl, ethyl, isopropyl) and C ₃ -C ₆ cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) C ₁ -C ₆ alkylene substituted by one, two or three substituents, preferably one or two substituents, for example C ₁ -C ₅ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₃ alkylene, C ₁ -C ₂ alkylene or C ₁ alkylene. In a preferred embodiment, V is C ₁ alkylene substituted with one or two, preferably one, C ₁ -C ₆ alkyl (eg methyl or ethyl) substituent.

According to the invention, R ² is H or C ₁ -C ₆ alkyl. In certain embodiments, R ² is H. In another embodiment, R ² is C ₁ -C ₆ alkyl, such as methyl, ethyl, isopropyl, butyl or t-butyl.

According to the invention, Z is unsubstituted C ₁ -C ₆ alkylene, for example unsubstituted C ₁ -C ₅ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₃ alkylene, C ₁ -C ₂ alkylene or C ₁ It is alkylene. In another aspect of the invention, Z is independently from C ₁ -C ₆ alkyl (eg methyl, ethyl, isopropyl) and C ₃ -C ₆ cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) C ₁ -C ₆ alkylene, for example C ₁ -C ₅ alkylene, C _1- , which is substituted by one, two or three substituents chosen, preferably one or two substituents C _{4 alkylene,} C 1 -C _{3 alkylene,} C 1 -C ₂ alkylene or _{C 1} alkylene. In a preferred embodiment, Z is C ₁ alkylene substituted with one or two C ₁ -C ₆ alkyl (eg methyl or ethyl) substituents. In another preferred embodiment, Z is C ₁ alkylene which is preferably substituted by one C ₃ -C ₆ cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

  In other embodiments, Z is a bond, eg, Z is absent.

According to one aspect of the invention, B is unsubstituted aryl, such as unsubstituted phenyl or naphthyl. In another embodiment B is aryl substituted with one, two or three substituents, preferably one or two substituents. The B substituent which may be referred to as one or more R groups is preferably -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, It is independently selected from -CN, aryl or -O aryl. Preferred substituted aryl moieties include phenyl and naphthyl, with phenyl being particularly preferred. In certain embodiments, the aryl is substituted with at least one substituent that is -OH. In some embodiments, the aryl is substituted with at least one substituent that is C ₁ -C ₆ alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl or hexyl. In another embodiment, the aryl is substituted with at least one substituent which is C ₁ -C ₆ haloalkyl, for example, —CF ₃ . In another embodiment, the aryl is substituted with at least one substituent that is halo, for example F, Cl or Br, and the F and Cl substituents are particularly preferred aryl substituents. In some embodiments, aryl, _-OC 1 -C ₆ alkyl, e.g., methoxy, ethoxy, propoxy, isopropoxy, substituted with at least substituent butoxy or t- butoxy. In still other embodiments, aryl, _-OC 1 -C ₆ haloalkyl, e.g., substituted with at least 1 substituent is -OCF _3. In certain embodiments, the aryl is substituted with at least one substituent that is -CN. In another embodiment, the aryl is substituted with another aryl moiety, such as at least one substituent which is a phenyl or naphthyl moiety. In one embodiment, the aryl is substituted with at least one substituent which is -Oaryl, for example -Ophenyl.

According to one aspect of the invention, B is unsubstituted C ₃ -C ₁₂ cycloalkyl, such as C ₃ cycloalkyl (eg, cyclopropyl), C ₄ cycloalkyl (eg, cyclobutyl), C ₅ cycloalkyl (eg, Cyclopentyl), C ₆ cycloalkyl (eg, cyclohexyl), C ₇ cycloalkyl (eg, bicyclo [2.2.1] heptanyl), C ₈ cycloalkyl (bicyclo [2.2.2] octanyl), C ₉ cyclocyclo Alkyl, C ₁₀ cycloalkyl (eg adamantyl), C ₁₁ cycloalkyl or C ₁₂ cycloalkyl. In certain embodiments, B is unsubstituted _C 3 -C ₆ cycloalkyl. In other embodiments, B is unsubstituted _C 7 _{-C 12} cycloalkyl or _C 7 _{-C 10} cycloalkyl.

In another embodiment B is C ₃ -C ₁₂ cycloalkyl substituted with one, two or three substituents, preferably one or two substituents. For example, in certain embodiments, B is substituted C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, C ₈ cycloalkyl, C ₉ cycloalkyl, C ₁₀ cycloalkyl, C ₁₁ cycloalkyl or C ₁₂ cycloalkyl. In other embodiments, B is a substituted _C 3 -C ₆ cycloalkyl. In other embodiments, B is a substituted _C 7 _{-C 12} cycloalkyl or _C 7 _{-C 10} cycloalkyl. The B substituent which may be referred to as one or more R groups is preferably -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, It is independently selected from -CN, aryl or -O aryl. Preferred _C 3 _{-C 12} cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl and adamantyl. In certain embodiments, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent that is —OH. In certain embodiments, the C ₃ -C ₁₂ cycloalkyl is at least one substituent which is C ₁ -C ₆ alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl or hexyl. It has been replaced. In another embodiment, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent which is C ₁ -C ₆ haloalkyl, for example, —CF ₃ . In another embodiment, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent that is halo, for example F, Cl or Br, and the F and Cl substituents are particularly preferred C ₃ -C ₁₂ cyclo. It is an alkyl substituent. In certain embodiments, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent that is —OC ₁ -C ₆ alkyl, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or t-butoxy. In still other embodiments, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent that is —OC ₁ -C ₆ haloalkyl, for example, —OCF ₃ . In certain embodiments, a C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent that is —CN. In another embodiment, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent which is an aryl moiety, eg, a phenyl or naphthyl moiety. In certain embodiments, the C ₃ -C ₁₂ cycloalkyl is substituted with at least one substituent which is —O aryl, eg, —O phenyl.

  The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas I and II.

The subformulae of Formula I and Formula II are where n is 2, Y is CH, W is CR ⁴ , V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. And a formula in which B is substituted or unsubstituted aryl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl, R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ^6A is present Or H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of formula IA and II-A is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IA and II-A.

The subformulae of Formula I or Formula II also have n = 2, Y is N, W is CR ⁴ , V is C ₁ alkylene, R ² is H, Z is C ₁ alkylene Wherein B is a substituted or unsubstituted aryl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl, R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ^6A is present Or H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of formulas IB and II-B is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IB and II-B.

The subformulae of Formula I and Formula II are those in which n is 2, Y is CH, W is N, V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. , And B is a substituted or unsubstituted aryl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl, R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ^6A is present Or H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of the formulas IC and II-C is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IC and II-C.

The subformulae of Formula I and Formula II are where n is 2, Y is N, W is N, V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. , And B is a substituted or unsubstituted aryl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl (eg, methyl), R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl , R ^6A is absent or is H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of formulas I-D and II-D is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas ID and II-D.

The subformulae of Formula I and Formula II are where n is 2, Y is CH, W is CR ⁴ , V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. And wherein B is a substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl, R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ^6A is present Or H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of the formulas IE and II-E is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IE and II-E.

The subformulae of Formula I and Formula II are those in which n is 2, Y is N, W is CR ⁴ , V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. And wherein B is a substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl, R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ^6A is present Or H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of formulas I-F and II-F is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IF and II-F.

The subformulae of Formula I and Formula II are those in which n is 2, Y is CH, W is N, V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. , B is a substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl, R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, and R ^6A is present Or H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of the formulas IG and II-G is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IG and II-G.

The subformulae of Formula I and Formula II are where n is 2, Y is N, W is N, V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. , B is a substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg,
Wherein X is CH, R ⁵ is H or C ₁ -C ₆ alkyl (eg, methyl), R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl , R ^6A is absent or is H or C ₁ -C ₆ alkyl. Another preferred embodiment of the compounds of formulas I-H and II-H is that X is N, R ⁵ is H or C ₁ -C ₆ alkyl and R ⁶ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, wherein R ^6A is absent or is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas I-H and II-H.

The subformulae of Formula I and Formula II are where n is 2, Y is CH, W is CR ⁴ , V is C ₁ alkylene, R ² is H, Z is a bond, Formulas in which B is substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg
[Wherein, X is CH and R ⁵ is H or C ₁ -C ₆ alkyl]. Other preferred embodiments of the compounds of the formulas I-J and II-J are those in which X is N and R ⁵ is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas I-J and II-J.

The subformulae of Formula I and Formula II are where n is 2, Y is N, W is CR ⁴ , V is C ₁ alkylene, R ² is H, Z is a bond, Formulas in which B is substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg
[Wherein, X is CH and R ⁵ is H or C ₁ -C ₆ alkyl]. Other preferred embodiments of the compounds of the formulas I-K and II-K are those in which X is N and R ⁵ is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas I-K and II-K.

The subformulae of Formula I and Formula II are those in which n is 2, Y is CH, W is N, V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. , B is a substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg,
[Wherein, X is CH and R ⁵ is H or C ₁ -C ₆ alkyl]. Other preferred embodiments of the compounds of the formulas IL and II-L are those in which X is N and R ⁵ is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IL and II-L.

The subformulae of Formula I and Formula II are where n is 2, Y is N, W is N, V is C ₁ alkylene, R ² is H, and Z is C ₁ alkylene. , B is a substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, eg,
Embedded image wherein X is CH and R ⁵ is H or C ₁ -C ₆ alkyl (eg methyl). Other preferred embodiments of the compounds of the formulas IM and II-M are those in which X is N and R ⁵ is H or C ₁ -C ₆ alkyl. In another embodiment, X is CH and T is CH. In some embodiments, X is N and T is CH. In another embodiment, X is CH and T is N. In another embodiment, X is N and T is N. The invention also encompasses pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of Formulas IM and II-M.

In another embodiment, the compounds of the present invention have human IDO IC ₅₀ values> 50 nM. In another embodiment, the compounds of the present invention have human IDO IC ₅₀ values ≦ 50 nM. In another embodiment, compounds of the present invention have human IDO IC ₅₀ values <5 nM.

Other Embodiments of the Invention In another embodiment, the present invention relates to one or more compounds of the invention and / or pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof A composition comprising the

  In another embodiment, the present invention provides a pharmaceutically acceptable carrier and a compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof Provided is a pharmaceutical composition comprising at least one.

  In another embodiment, the present invention provides a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or Provided are pharmaceutical compositions comprising at least one of the solvates.

  In another embodiment, the present invention provides a method of producing a compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof.

  In another embodiment, the present invention provides an intermediate for the production of a compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof Do.

  In another embodiment, the present invention comprises a therapeutically effective amount of one or more of the compounds of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof alone or Various types of cancer, viral infections, optionally administered in combination with other compounds of the invention and / or at least one other type of therapeutic agent such as a chemotherapeutic agent or a signal transducer inhibitor. And / or provide methods of treating and / or preventing autoimmune disease.

  In another embodiment, the present invention provides a compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof for use in therapy.

  In another embodiment, the present invention relates to a compound of the present invention and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof for simultaneous, separate or sequential use, Provided is a combined preparation of a further therapeutic agent.

  In another embodiment, the present invention relates to a compound of the present invention and / or a pharmaceutical thereof for simultaneous, separate or sequential use in the treatment and / or prevention of multiple diseases or disorders associated with the enzymatic activity of IDO. A combination formulation of a pharmaceutically acceptable salt, a stereoisomer thereof or a tautomer thereof and a further therapeutic agent is provided.

  In another aspect, the invention provides a method of treating a patient having or predisposed to a medical condition that can be affected by the enzymatic activity of IDO. Many medical conditions can be treated. The method comprises administering to the patient a composition comprising a therapeutically effective amount of a compound described herein and / or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof. For example, the compounds described herein may be used to treat or prevent viral infections, proliferative diseases (eg, cancer) and autoimmune diseases.

Therapeutic Applications The compounds and pharmaceutical compositions of the invention are useful for the treatment or prevention of any disease or condition that may be affected by the enzymatic activity of IDO. These include viruses and other infections (eg skin infections, GI infections, urinary tract infections, urogenital infections, systemic infections), proliferative diseases (eg cancer) and autoimmune diseases (eg rheumatoid arthritis, epilepsy) including. The compounds and pharmaceutical compositions may be administered to animals, preferably mammals (eg, domesticated animals, cats, dogs, mice, rats), more preferably humans. Any method of administration may be used for delivery of the compound or pharmaceutical composition to the patient. In one embodiment, the compound or pharmaceutical composition is administered orally. In another embodiment, the compound or pharmaceutical composition is administered parenterally.

  The compounds of the present invention can modulate the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). The term "modulate" is intended to refer to the ability to increase or decrease the activity of an enzyme or receptor. Thus, the compounds of the present invention may be used in methods of modulating IDO by contacting an enzyme with any one or more of the compounds or compositions described herein. In certain embodiments, compounds of the present invention may act as inhibitors of IDO. In a further embodiment, a compound of the invention is used to modulate the activity of IDO by administering a modulating (eg, inhibiting) amount of a compound of the invention to a cell or individual in need of modulation of an enzyme. It can.

  The compounds of the present invention can inhibit the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). For example, the compounds of the invention can be used to inhibit the activity of IDO by administering an inhibitory amount of a compound of the invention to cells or individuals in need of modulation of the enzyme.

  The invention further provides a method of inhibiting the degradation of tryptophan in a system comprising cells expressing IDO, such as a tissue, a living organism or a cell culture. In certain embodiments, the invention provides methods of altering (eg, increasing) extracellular tryptophan levels in a mammal by administering an effective amount of a compound or composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are conventional in the art.

  The invention further provides a method of blocking immunosuppression, such as IDO mediated immunosuppression, in a patient by administering to the patient an effective amount of a compound or composition described herein. IDO-mediated immunosuppression is associated with, for example, cancer, tumor growth, metastasis, viral infection and viral replication.

  The present invention is further directed to a method of treating a disease associated with activity or expression, including aberrant activity and / or overexpression of IDO in an individual (eg, a patient), wherein the individual is in need of such treatment. Methods are provided by administering an effective amount or dose of a compound of the invention or a pharmaceutical composition thereof. An example disease may include any disease, disorder or condition directly or indirectly associated with expression or activity such as overexpression or aberrant activity of IDO enzymes. IDO related diseases may also include any disease, disorder or condition that can be prevented, alleviated or cured by modulation of enzyme activity. Examples of IDO related diseases include cancer, viral infections such as HIV infection, HCV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataract, organ transplantation (eg, organ graft rejection) And autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosus.

  The term "cell" as used herein is intended to refer to a cell that is in vitro, ex vivo or in vivo. In certain embodiments, ex vivo cells can be part of a tissue sample excised from an organism such as a mammal. In one embodiment, the in vitro cells can be cells in cell culture. In one embodiment, the in vivo cells are cells surviving in an organism such as a mammal.

  The term "contacting" as used herein refers to bringing together the specified moieties in an in vitro or in vivo system. For example, "contacting" an IDO enzyme with a compound of the invention involves administering the compound of the invention to an individual or patient such as a human with IDO, and, for example, preparing a cell or purified preparation containing an IDO enzyme of the compound of the invention Includes introduction to the sample containing the substance.

  The term "IDO inhibitor" refers to an agent that can inhibit the activity of indoleamine 2,3-dioxygenase (IDO), thereby reversing IDO mediated immunosuppression. IDO inhibitors can inhibit IDO1 and / or IDO2 (Indol 1). IDO inhibitors may be reversible or irreversible IDO inhibitors. A "reversible IDO inhibitor" is a compound that reversibly inhibits IDO enzyme activity at the catalytic or non-catalytic site, and an "irreversible IDO inhibitor" is a compound that irreversibly destroys IDO enzyme activity .

  Types of cancer that can be treated with compounds of the present invention include brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, hematologic cancer, lung cancer and bone cancer. It is not limited to these. Examples of such cancer types are intestinal cancer such as neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer and hereditary non-polyposis colorectal cancer, esophagus cancer, lip cancer, laryngeal cancer, hypopharynx Cancer, tongue cancer, salivary adenocarcinoma, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, Pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urological cancer, melanoma, glioblastoma, astrocytoma, meningioma, brain tumors such as medulloblastoma and peripheral neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's Lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), adult T cell leukemia lymphoma, generalized large B cell Lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small Cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, seminoma, rhabdomyosarcoma, craniopharynoma, osteosarcoma, chondrosarcoma, myosoma , Liposarcoma, fibrosarcoma, Ewing sarcoma and plasmacytoma.

  Therefore, according to another embodiment, the present invention provides a method of treating an autoimmune disease by providing a compound or composition of the present invention to a subject in need thereof. Examples of such autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus, Sharp syndrome, Crest syndrome (calcification, Raynaud's syndrome, esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis (Wegener's disease) And collagen disease such as Sjögren's syndrome, Goodpasture syndrome, renal disease such as rapidly progressing glomerulonephritis and membranoproliferative glomerulonephritis type II, type I diabetes, autoimmune polyglandular endocrine failure / candidiasis · Endocrine diseases such as ectodermal dystrophy (APECED), autoimmune parathyroidism, anemia, gonadal dysfunction, idiopathic Addison's disease, hyperthyroidism, Hashimoto's thyroiditis and primary myxedema, pemphigus vulgaris, Skin diseases such as pemphigus, gestational herpes zoster, epidermolysis bullosa and severe type erythema, primary biliary cirrhosis, self-elimination Cholangitis, autoimmune hepatitis 1, autoimmune hepatitis 2, liver disease such as primary sclerosing cholangitis, multiple sclerosis, myasthenia gravis, myasthenia gravis Lambert-Eaton syndrome, acquired nerve Myopathy, Guillain-Barre syndrome (Müller-Fisher syndrome), stiff man syndrome, cerebellar degeneration, ataxia, neurologic diseases such as oculoclonic, sensory neuropathy and achalasia, autoimmune hemolytic anemia, idiopathic thrombocytopenia It includes, but is not limited to, blood diseases such as purpura (Welchoff's disease) and infections with autoimmune reactions such as AIDS, malaria and Chagas disease.

  For example, antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapies (eg IL2 and GM-CSF) and / or tyrosine kinase inhibitors etc. Or one or more additional agents or treatment methods may optionally be used in combination with the compounds of the invention for the treatment of IDO related diseases, disorders or conditions. The agents may be combined with the present compounds in a single dosage form, or the agents may be administered simultaneously or sequentially in separate dosage forms.

  Suitable chemotherapeutic agents or other anticancer agents are, for example, uracil mustard, chlormetin, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine Alkylating agents of busulfan, carmustine, lomustine, streptozocin, dacarbazine and temozolomide (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) It is not limited to.

  Agents suitable for use in combination with the compounds of the invention in the treatment of melanoma optionally include carmustine (BCNU) and other chemotherapeutics such as cisplatin, dacarbazine (DTIC); DTIC, BCNU, cisplatin and "Dartmus regimen" consisting of tamoxifen; including, but not limited to, a combination of Cisplatin, vinblastine and DTIC, Temozolomide or Yerboi®. The compounds of the invention may also be combined with immunotherapeutic agents including cytokines such as interferon alpha, interleukin 2 and tumor necrosis factor (TNF) in the treatment of melanoma.

  The compounds of the invention may also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are in some respects similar to antiviral vaccines used for the prevention of diseases caused by viruses such as polio, measles and mumps. A weakened melanoma cell, or a portion of a melanoma cell called an antigen, can be injected into a patient to stimulate the body's immune system to destroy the melanoma cells.

  Melanomas localized to the arms or legs may also be treated using thermal isolation limb perfusion therapy with a combination of agents comprising one or more compounds of the present invention. This treatment protocol temporarily separates the associated limb circulation from the rest of the body and injects high doses of chemotherapy into the arteries supplied to the limb, thus causing otherwise serious side effects Provide a high dose to the tumor area without exposing internal organs to such doses that should be. Typically, the fluid is warmed to 102 ° -104 ° F. Melphalan is the most frequently used drug for this chemotherapy. This can be done with another agent called tumor necrosis factor (TNF).

  Suitable chemotherapeutic agents or other anti-cancer agents are for example anti-metabolites (folate antagonists (folate antagonists such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine) Pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, including, but not limited to).

  Suitable chemotherapeutic agents or other anti-cancer agents are furthermore, for example, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol), mithramycin, deoxycophorol. Natural products such as mycin, mitomycin-C, L-asparaginase, interferon (in particular IFN-a), etoposide and teniposide or derivatives thereof (e.g. vinca alkaloid, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) Including.

  Other cytotoxic agents include navelbin, CPT-11, anastrozole, letrozole, capecitabine, raloxifene and droloxifene.

  Also suitable are epipodophyllotoxins; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; anti-hormonal therapeutics Leucovorin; tegafur; and cytotoxic agents such as hematopoietic growth factors.

  Other anticancer agents include antibody therapeutic agents such as antibodies against costimulatory molecules such as trastuzumab (Herceptin®), CTLA-4, 4-1BB and PD-1 or antibodies against cytokines (IL-10 or TGF-β) including.

  Also included are other anticancer agents that block immune cell migration, such as antagonists of chemokine receptors, including CCR2 and CCR4.

Also included are adjuvants or other anti-cancer agents that enhance the immune system, such as adoptive T cell transfer.

  Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

  The pharmaceutical composition of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more important steps in the signal transduction pathway in the normal function of cancer cells, thereby resulting in apoptosis. Suitable STIs include (i) bcr / abl kinase inhibitors such as, for example, STI 571 (Gleevec®); (ii) eg kinase inhibitors (Iressa®, SSI-774) and antibodies ( Epidermal growth factor (EGF) receptor inhibitors such as Imclone: C 225 [Goldstein et al., Clin. Cancer Res., 1: 1311-1318 (1995)] and Abgenix: ABX-EGF); (iii) eg Her-2 / neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as L-744, 832 (Kohl et al., Nat. Med., 1 (8): 792-797 (1995)); iv) For example, inhibitors of Akt family kinases such as rapamycin or inhibitors of the Akt pathway (see, eg, Sekulic et al., Cancer Res., 60: 3504-3513 (2000)); (v) eg, flavopyridol and UCN- Cell cycle kinase inhibitors such as O1 (e.g. Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3: 47-56 (2003) And (vi) including but not limited to phosphatidylinositol kinase inhibitors such as, for example, LY 294002 (see, for example, Vlahos et al., J. Biol. Chem., 269: 5241-5248 (1994)). I will not. Alternatively, the at least one STI and the at least one IDO inhibitor may be in separate pharmaceutical compositions. In certain embodiments of the invention, at least one IDO inhibitor and at least one STI may be administered to the patient simultaneously or separately. In other words, at least one IDO inhibitor may be administered first, at least one STI may be administered first, or at least one IDO inhibitor and at least one STI may be administered simultaneously. Furthermore, when more than one IDO inhibitor and / or STI is used, these compounds may be administered in any order.

  The invention further provides a chronic virus in a patient, comprising at least one IDO inhibitor, optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent in a pharmaceutically acceptable carrier. Provided are pharmaceutical compositions for the treatment of infections. The pharmaceutical composition may comprise, in addition to the at least one established (known) IDO inhibitor, at least one IDO inhibitor according to the invention. In certain embodiments, at least one of the IDO inhibitors of the pharmaceutical composition is selected from the group consisting of compounds of Formulas I and II.

  Also provided is a method of treating chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.

  In certain embodiments of the invention, at least one IDO inhibitor and at least one chemotherapeutic agent may be administered to a patient simultaneously or sequentially. In other words, at least one IDO inhibitor may be administered first, at least one chemotherapeutic agent may be administered first, or at least one IDO inhibitor and at least one STI may be administered simultaneously. Furthermore, when more than one IDO inhibitor and / or chemotherapeutic agent is used, these compounds may be administered in any order. Similarly, any antiviral agent or STI may be administered at any time for administration of the IDO inhibitor.

  Chronic viral infections that can be treated using this combination treatment include hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus These include, but are not limited to, diseases caused by (EBV), Varicella zoster virus, Coxsackie virus, human immunodeficiency virus (HIV). Notably, parasitic infections (eg, malaria) may also be treated by the methods described above, optionally with the addition of compounds known to treat parasitic conditions instead of antiviral agents.

  In yet another embodiment, a pharmaceutical composition comprising at least one IDO inhibitor of the present invention may be administered to a patient for the prevention of arterial restenosis, such as after balloon endoscopy or stent placement. In certain embodiments, the pharmaceutical composition further comprises at least one taxane (eg, paclitaxel (taxol); see, eg, Scheller et al., Circulation, 110: 810-814 (2004)).

  Suitable antiviral agents contemplated for use in combination with the compounds of the invention include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other anti-antibodies It may contain a viral agent.

  Examples of suitable NRTIs are zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis (POM)-PMEA]; (BMS-180194); BCH-I 0 652; emtricitabine [(-)-FTC]; beta-L-FD4 (also known as beta-L-D4C and the name beta-L-2 ', 3'-dicreoxy-5-fluoro-cytidine) DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and rodenosin (FddA). Typical suitable NNRTIs are nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1- (ethoxy-) And (+)-calanolide A (NSC-675451) and B. methyl) -5- (1-methylethyl) -6- (phenylmethyl)-(2,4 (1H, 3H) -pyrimidinedione); Typical suitable protease inhibitors are saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141 W94); lacinavir (BMS-) DMP-450; BMS-2322623; ABT-378; and AG-1549.Other antiviral agents include: Hydroxyurea, Ribavirin, IL-2, IL-12, Pentafuside and Yissum Project No. 11607.

Also provided herein is a method of treatment, wherein a compound of Formula I or Formula II is administered with one or more immunoneoplastic agents. The immunoneoplastic agents used herein, also known as cancer immunotherapies, are effective at enhancing, stimulating and / or upregulating the immune response in a subject.

  In certain embodiments, a compound of Formula I or Formula II is administered sequentially prior to administration of the immunoneoplastic agent. In another embodiment, a compound of Formula I or Formula II is co-administered with an immunoneoplastic agent. In yet another embodiment, a compound of Formula I or Formula II is administered sequentially after administration of the immunoneoplastic agent.

  In other embodiments, a compound of Formula I or Formula II may be co-formulated with an immunoneoplastic agent.

  Immunoneoplastic agents include, for example, small molecule drugs, antibodies or other biological or small molecules. Examples of biological immunoneoplastic agents include, but are not limited to, cancer vaccines, antibodies and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is humanized or human.

  In one embodiment, the immunoneoplastic agent is (i) a stimulator (including co-stimulatory) receptor agonist of T cells or (ii) a signal antagonist (including co-inhibition), both of which are antigen-specific T cell responses (Also often referred to as immune checkpoint regulators).

  Some of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7 family including B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, such as CD40 and CD40L, OX-40, OX-40L, CD70, CD27L. , CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin α / NFβ, including TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, the NGFR.

  In other embodiments, the immunoneoplastic agent is a cytokine that inhibits T cell activation (eg, IL-6, IL-10, TGF-β, VEGF and other immunosuppressive cytokines) or for immune response stimulation. It is a cytokine that stimulates T cell activation.

  In certain embodiments, the T cell response comprises a compound of Formula I or Formula II and one or more (i) CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, Proteins that inhibit T cell activation such as CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4 (eg, Antagonists of immune checkpoint inhibitors) and (ii) B7-1, B7-2, CD28, 4-1BB (CD137), 4-1 BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27 , Agonists of proteins that stimulate T cell activation such as CD40, DR3 and CD28H It can be stimulated by the combination.

  Other agents which may be combined with compounds of Formula I or Formula II for the treatment of cancer include antagonists of inhibitory receptors of NK cells or agonists of activating receptors of NK cells. For example, a compound of Formula I or Formula II may be combined with a KIR antagonist such as lyrilumab.

  Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, and RG 7155 (WO 11/70024, WO 11/107553, WO 11/131407, WO 13/87699, WO 13/119716, WO 13/132044) Or CSF-1R antagonists such as CSF-1R antagonist antibodies, including but not limited to FPA-008 (WO 11/140249, WO 13/169264, WO 14/036357).

  In another embodiment, a compound of formula I or formula II, an agonist agent that ligates a positive costimulatory receptor, a blocking agent that attenuates signal transduction via an inhibitory receptor, an antagonist and an anti-tumor T cell appearance frequency throughout the body One or more agents that raise sex, agents that overcome another immunosuppressive pathway within the tumor microenvironment (eg, inhibitory receptor binding block (eg, PD-L1 / PD-1 interaction), Treg depletion or inhibition (eg, Anti-CD25 monoclonal antibody (eg by daclizumab) or by ex vivo anti-CD25 bead depletion, metabolic enzyme inhibition such as IDO or T cell anergy or exhaustion recovery / prevention) and innate immune activation and / or inflammation at the tumor site It may be used with one or more of the inducing agents.

  In certain embodiments, the immunoneoplastic agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, JABOY® (ipilimumab) or tremelimumab.

  In other embodiments, the immunoneoplastic agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo (R) (nivolumab), Chitoluda (R) (penbrolizumab) or MEDI-0680 (AMP-514; WO 2012/145493). Although the immunoneoplastic agent may also include pidilizumab (CT-011), the specificity of PD-1 binding is questioned. Another attempt to target the PD-1 receptor is a recombinant protein called AMP-224, consisting of the extracellular domain (B7-DC) of PD-L2 fused to the Fc portion of IgG1.

  In other embodiments, the immunoneoplastic agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL 3280A (RG 7446; WO 2010/077634), Durbarumab (MEDI 4736), BMS-936559 (WO 2007/005874) and MSB 0010718 C (WO 2013/79174).

  In other embodiments, the immunoneoplastic agent is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO 10/19570, WO 14/08218) or IMP-731 or IMP-321 (WO 08/132601, WO 09/44273).

  In another embodiment, the immunoneoplastic agent is a CD137 (4-1BB) agonist such as an antagonist CD137 antibody. Suitable CD137 antibodies include, for example, urerumab and PF-05082566 (WO 12/32433).

  In other embodiments, the immunoneoplastic agent is a GITR agonist such as an antagonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06/105021, WO 09/009116) and MK-4166 (WO 11/028683).

  In another embodiment, the immunoneoplastic agent is an IDO antagonist. Suitable IDO antagonists are, for example, INCB-024360 (WO 2006/122150, WO 07/75598, WO 08/36653, WO 08/36642), Indoximod or NLG-919 (WO 09/73620, WO 09/156652, WO 11/56652, WO 12/142237) )including.

  In another embodiment, the immunoneoplastic agent is an OX40 agonist, such as an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

  In another embodiment, the immunoneoplastic agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO 06/029879).

  In other embodiments, the immunoneoplastic agent is a CD40 agonist, such as an antagonist CD40 antibody. In yet another embodiment, the immunoneoplastic agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, luctumumab or dacetuzumab.

  In other embodiments, the immunoneoplastic agent is a CD27 agonist, such as an antagonist CD27 antibody. Suitable CD27 antibodies include, for example, barrilumab.

  In another embodiment, the immunoneoplastic agent is MGA 271 (against B7H3) (WO 11/109400).

  The invention also includes one or more containers comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, for example for the treatment or prevention of IDO related diseases or disorders, obesity, diabetes and other diseases described herein. And a pharmaceutical kit useful for Such kits may, as will be readily apparent to those skilled in the art, further optionally, for example, one or more of various conventional pharmaceutical kits such as a container comprising one or more pharmaceutically acceptable carriers, an additional container, etc. It may further include an element. Instructions may also be included in the kit as an insert or as a label indicating the amount of ingredient to be administered, an indication of administration and an indication of administration and / or mixing of ingredients.

  Combination therapy includes administration of these therapeutic agents in a sequential manner, ie, administration of each therapeutic agent at different times, and administration of at least two of the therapeutic agents or therapeutic agents in a substantially simultaneous manner. Intended. Substantial co-administration can be achieved, for example, by administering to the subject a single dosage form comprising each therapeutic agent at a fixed ratio, or multiple single dosage forms for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent may be performed by any suitable route including, but not limited to, oral, intravenous, intramuscular and direct absorption from mucosal tissue. These therapeutic agents may be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination may be administered by intravenous injection, and the other therapeutic agent of the combination may be administered orally. Alternatively, for example, the entire therapeutic agent may be administered orally or the entire therapeutic agent may be injected intravenously. Combination therapy may also include combining the administration of the above therapeutic agents with other biologically active ingredients and non-drug treatments (eg, surgery or radiation treatment). When the combination therapy further comprises non-drug treatment, non-drug treatment may be performed at any suitable time as long as the beneficial effect is achieved by the combination of the therapeutic agent and non-drug treatment combination. For example, in appropriate instances, the beneficial effects are still achieved with the non-drug treatment being separated in time from the administration of the therapeutic agent for several days or weeks.

Pharmaceutical Compositions and Administration The present invention is also formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents and optionally one or more additional therapeutic agents as described above, in a therapeutically effective amount Also provided are pharmaceutically acceptable compositions comprising one or more compounds of Formula I and / or Formula II.

  The compounds of the present invention may be used in any suitable manner, using, for example, tablets, capsules (each including sustained release or timed release formulations), pills, tablets, using any of the uses described herein. Oral, such as powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; subcutaneous, intravenous, intramuscular or Non-enteral (eg as sterile injectable aqueous or non-aqueous solution or suspension), such as by intrasternal injection or infusion techniques; intranasal administration including administration to the nasal mucosa, such as by inhalation spray; cream or ointment form etc Or rectally, such as in the form of a suppository. They may be administered alone, but generally are administered with a pharmaceutical carrier, selected based on the chosen route of administration and standard pharmaceutical practice.

  The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, human beings at a reasonable benefit / risk ratio, without undue toxicity, irritation, allergic responses or other problems or complications. And are used herein to refer to compounds, substances, compositions and / or dosage forms suitable for use in contact with animal tissues.

  The term "pharmaceutically acceptable carrier" as used herein refers to a liquid or solid bulking agent involved in the transport or transport of the subject compound from one organ or body part to another organ or body part. A pharmaceutically acceptable substance, composition or vehicle, such as a diluent, additive, manufacturing aid (eg, lubricant, talc, magnesium stearate, calcium or zinc stearate or stearic acid) or a solvent-encapsulated substance means. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.

  The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" is thus depending on the mode of administration and the nature of the administration form, diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents Generally accepted in the art for delivery of biologically active agents to animals, particularly mammals, including agents, flavors, fragrances, antibacterials, antifungals, lubricants and dispersants, etc. Media that

  Pharmaceutically acceptable carriers are formulated with a number of factors well within the purview of those skilled in the art. These include, but are not limited to, the type and nature of the active agent to be formulated, the subject to which the drug-containing composition is administered, the intended route of administration of the composition and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media as well as various solid and semi-solid dosage forms. Such carriers may contain, in addition to the active agent, a number of different ingredients and additives, such additional ingredients for various reasons in the formulation, eg, as is known to the person skilled in the art. Are included as stabilizers, binders and the like. For a description of suitable pharmaceutically acceptable carriers and factors involved in selection, see, for example, Allen, Jr., LV et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press 2012) can be seen in a variety of readily available materials.

  The regimen of administration of the compounds of the invention will, of course, be based on the pharmacodynamics of the particular drug as well as the mode and route of its administration, the species of recipient, age, gender, health, medical condition and weight, nature and degree of symptoms, combination It depends on known factors such as the type of treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient and the desired effect.

  As a general guide, the daily oral dose of each active ingredient, when used for the effects described, is about 0.001 to about 5000 mg / day, preferably about 0.01 to about 1000 mg / day, most preferably Is in the range of about 0.1 to about 250 mg / day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during constant rate infusion. The compounds of the invention may be administered in unit daily doses or the total daily dose may be administered in divided doses twice, three times or four times daily.

  The compounds are generally intended to be in the form of administration intended, for example oral tablets, capsules, elixirs and syrups and appropriate pharmaceutical diluents, additives or carriers appropriately selected according to the customary practice (collectively referred to as pharmaceutical carriers herein). In combination with

  Dosage forms (pharmaceutical compositions) suitable for administration can comprise from about 1 milligram to about 2000 milligrams of active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.

  A typical capsule for oral administration contains at least one of the compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is sieved through a 60 mesh sieve and filled into a No. 1 gelatin capsule.

  A typical injectable preparation is produced by aseptically placing at least one (250 mg) of a compound of the present invention in a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of saline to produce an injectable formulation.

  The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds according to the invention, alone or in combination with a pharmaceutical carrier. If desired, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents, such as anti-cancer agents or other pharmaceutically active substances.

  Regardless of the route of administration chosen, suitable hydrated forms and / or compounds of the invention which may be used in the pharmaceutical composition of the invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. Formulate.

  The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration without becoming toxic to the patient. It can be varied to obtain the amount of ingredients.

  The dosage level chosen is the activity of the particular compound of the invention or its ester, salt or amide used, the route of administration, the time of administration, the excretion or metabolism rate of the particular compound used, the rate and extent of absorption, the duration of treatment, the particular treatment used And other drugs, compounds and / or substances used in combination with the compound, age, sex, weight, condition, general health and past medical history of the patient to be treated and similar factors well known in the pharmaceutical art, Due to various factors.

  An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may begin with a dose of a compound of the present invention in the lower levels of the pharmaceutical composition that is necessary to achieve the desired therapeutic effect, and gradually reverse the dose until the desired effect is achieved. To increase

  In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective doses generally depend on the factors described above.

  Optionally, an effective daily dose of the active compound may be administered in unit dose forms, optionally in two, three, four, five, six or more intervals at appropriate intervals throughout the day May be administered at In one embodiment of the invention, the administration is once daily.

  While it is possible to administer the compounds of the invention in a single dose, it is preferred to administer the compounds as a pharmaceutical preparation (composition).

Definitions Unless otherwise stated, the singular may also include the plural. For example, "a" may refer to one or more.

  Unless otherwise stated, any heteroatom having an unsaturated valence is considered to have sufficient hydrogen atoms to satisfy valency.

  Throughout the specification and the appended claims, certain chemical formulas or names encompass all stereoisomers and optical isomers and their racemates, when such isomers exist. Unless stated otherwise, all chiral (enantiomers and diastereomers) and racemates are within the scope of the present invention. Many geometric isomers of C = C double bonds, C = N double bonds, ring systems and the like can also exist in the present compounds, and all such stable isomers are contemplated in the present invention. The cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention are described and may be isolated as a mixture of isomers or as separate isomeric forms. The compounds can be isolated in optical activity or in racemic form. Optically active forms can be prepared by resolution of racemates or synthesis from optically active starting materials. All methods used in the preparation of the compounds and intermediates of the present invention are taken as part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated in the customary manner, for example by chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the present invention. If so desired, one form of the compound may be converted to another. The free base or acid may be converted to a salt, the salt may be converted to a free compound or other salt, and the isomeric mixture of compounds of the invention may be separated into individual isomers. The compounds of the present invention, free forms and salts thereof, can exist in multiple tautomeric forms, in which a hydrogen atom is transferred to another part of the molecule and the chemical bond between the atoms of the molecule is consequently rearranged. It should be understood that all tautomeric forms are within the scope of the present invention as long as they can exist.

Symbols, in accordance with clarity and standard practice in the field
Is used in the formulas and tables to indicate the bond that is the attachment point of a moiety or substituent to the core / core of the structure.

Furthermore, for the sake of clarity, when a substituent has a dash (-) that is not between two letters or symbols, this is used to indicate the point of attachment of the substituent. For example, -CONH ₂ is attached through the carbon atom.

Furthermore, for the sake of clarity, when no substituent is shown at the end of the solid line, this indicates that there is a methyl (CH ₃ ) group attached to the bond.

As used herein, the terms "alkyl" and "alkylene" (also referred to as "alk") are intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms . For _{example, "C} 1 -C ₆ alkyl" or _{"C 1-6} alkyl" means an alkyl having 1 to 6 carbon atoms. Examples of alkyl groups are methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, t-butyl) and pentyl (eg n-pentyl, (Including isopentyl and neopentyl), but is not limited thereto. _"C 1 -C ₆ alkylene" refers to alkylene having 1 to 6 carbon atoms. Examples of alkylene groups include methylene (-CH ₂ -), ethylene _(-CH 2 CH ₂ -) including such as, but not limited to.

  As used herein, "aryl" refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl.

  "Halo" or "halogen" includes fluoro, chloro, bromo and iodo.

  "Haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl I will not. Examples of haloalkyl also include "fluoroalkyl", which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more fluorine atoms. .

The term "cycloalkyl" refers to a hydrocarbon ring that is fully saturated having the recited number of ring atoms, eg, C ₃ -C ₆ cycloalkyl or C ₃ -C ₁₂ cycloalkyl. "Cycloalkyl" is also intended to refer to bicyclic and polycyclic hydrocarbons such as, for example, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and adamantyl. C _3-6 cycloalkyl _is intended to include C _3, C 4, _{C 5} and _{C 6} cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl.

  As used herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group as long as normal valence is maintained and the substitution results in a stable compound.

  As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds, wherein the parent compound is modified by the preparation of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid phosphoric acid and nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid Malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfone Included are salts prepared from organic acids such as acid, ethanedisulfonic acid, oxalic acid and isethionic acid.

  The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts may be prepared by reaction of these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two, generally Nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Allen, Jr., L.V., ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012). The disclosure of which is incorporated herein by reference.

Additionally, the compounds of Formula I and Formula II may have prodrug forms. Within the scope and spirit of the present invention, any compound that converts in vivo to provide a bioactive agent (ie, a compound of Formula I or II) is a prodrug. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives,
a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985) and Widder, K. et al., eds., Methods in Enzymology, 112: 309-396, Academic Press (1985);
b) Bundgaard, H., Chapter 5: "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 113-191, Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991 );
c) Bundgaard, H., Adv. Drug Deliv. Rev., 8: 1-38 (1992);
d) Nielsen, NM et al., J. Pharm. Sci., 77: 285 (1988);
e) Kakeya, N. et al., Chem. Pharm. Bull., 32: 692 (1984); and g) Rautio, J. ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011)
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Compounds containing a carboxy group can form physiologically hydrolyzable esters which act as prodrugs to be hydrolyzed in the body to give a compound of formula I or formula II itself. Such prodrugs are preferably administered orally, as hydrolysis in many situations mainly occurs under the influence of digestive enzymes. Parenteral administration may be used where the ester itself is active or hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I or formula _{II, C 1-6 alkyl, C 1-6} alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, _{methoxymethyl, C 1-6} alkanoyloxy - C _1-6 alkyl (eg, acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C _1-6 alkoxycarbonyloxy-C _1-6 alkyl (eg, methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, gly) Siloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolene-4-yl) -methyl) and other well known compounds used, for example, in the penicillin and cephalosporin field. Containing physiologically hydrolysable esters of Such esters can be prepared by conventional techniques known in the art.

  The preparation of prodrugs is well known in the art and is described, for example, in King, FD, ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (Second Edition, reproduced, 2006); Testa, B. et al. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice of Medicinal Chemistry, Third Edition, Academic Press, San. Described in Diego, CA (2008).

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include atoms having the same atomic number but different mass numbers. As a non-limiting general example, isotopes of hydrogen include deuterium and tritium. Carbon isotopes include ¹³ C and ¹⁴ C. Isotopically-labeled compounds of the present invention can generally be replaced by any suitable isotopically-labeled reactant in place of any other unlabeled reactant by conventional methods known to those skilled in the art or as described herein. It can be used and manufactured.

  The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association involves hydrogen bonding. In some cases, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystalline lattice of the crystalline solid. The solvent molecules of the solvate may be present in a regular and / or non-regular arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" includes both solution-phase and isolatable solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Methods of solvation are generally known in the art.

  The term "patient" as used herein refers to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (eg, mice, apes, horses, cows, pigs, dogs, cats and the like), but are not limited thereto, and most preferably refer to humans.

  The term "effective amount" as used herein refers to a drug or agent that elicits a biological or medical response in a tissue, system, animal or human, for example, as sought by a researcher or physician, ie, the present invention Mean the amount of the compound. Furthermore, the term "therapeutically effective amount" refers to the treatment, cure, prevention or alleviation of amelioration of the disease, disorder or side effect, or reduction of the rate of progression of the disease or disorder as compared to a corresponding subject not receiving such an amount Refers to any amount to bring. An effective amount can be administered in one or more administrations, applications or doses, and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.

  The term "treatment" as used herein includes any effect, eg, reduction, reduction, reduction, modulation, amelioration or elimination, which results in the amelioration of the condition, disease, disorder or the like or the amelioration of its symptoms.

  For therapeutic use, the compound salts of the present invention are contemplated as pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also be useful, for example, in the preparation or purification of a pharmaceutically acceptable compound.

  The compounds of the present invention can be prepared by methods as illustrated in the following schemes utilizing chemical transformations known to those skilled in the art. Solvents, temperatures, pressures and other reaction conditions can be readily selected by one skilled in the art. Starting materials are commercially available or readily prepared by one skilled in the art. These schemes are illustrative and are not intended to limit the techniques that one skilled in the art can potentially use to prepare the compounds disclosed herein. Various methods may be apparent to those skilled in the art. Furthermore, the various steps in the synthesis may be performed in a different order or sequence to obtain the desired compounds. Furthermore, the reactions shown as separate steps in these schemes are carried out either directly, sequentially incorporating multiple steps in the same reaction vessel, or without multiple purification or identification of intermediates. Does not exclude that production takes place. In addition, many of the compounds prepared in the following manner can be further modified using conventional chemistry well known to those skilled in the art.

  See also International Applications PCT / US2015 / 059271, PCT / US2015 / 059311 and PCT / US2015 / 059316.

  These chemical transformations used herein include Smith, MB et al., March's Advanced Organic Chemistry Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, New York (2001) or other synthetic organic chemistry papers or standard references. You can refer to the Certain transformations may require that reactive functional groups be masked with protecting groups. A convenient reference describing the functionality for the introduction, removal and related reaction conditions of these groups is Greene, TW et al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York (1999) .

  Schemes 1-3 describe the preparation of compounds of formula I. These methods can also be applied to the preparation of the compounds of the present invention.

Treatment of the phosphonoacetate ester (IV) with a base such as sodium hydride (Scheme 1) in a solvent such as THF followed by a ketone of general structure III gives the trisubstituted olefin. The substituted analogs of IV (R ⁴ is not H) yield tetrasubstituted olefins. This method and the further methods described below are transformations well known to those skilled in the art of organic / pharmaceutical chemistry. The following alternative methods of olefination and conversion are also known and selected by those skilled in the art based on their applicability to the particular substrate under consideration. The reduction is achieved by stirring or shaking a solution of the olefin in a suitable solvent in the presence of a catalyst, usually palladium carbon, under 1 atmosphere or more of H ₂ . Hydrolysis of the ketal group gives ketones of general structure V. Generally, this is achieved by heating in the presence of an aqueous acid solution such as HCl and a cosolvent such as THF. In addition to the cyclic ethylene glycol-based ketals of the formula, other cyclic and non-cyclic ketal protecting groups are used. The ketone is deprotonated with a base such as LiHMDS and reacted with N-phenyltrifluoromethanesulfonimide or similar reactants to give a triflate of general structure VI. These triflates are coupled with a boronic acid such as VII or an ester Ar-B (OR) ₂ and Suzuki coupling (T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem., 1995, 60, 7508-7510 ) To obtain a coupling product. This reaction is known in many variants but generally involves heating the two reactants and a catalyst such as (Ph ₃ P) ₄ Pd in a solvent such as DMF with a base such as aqueous potassium carbonate . Reduction of the olefin affords intermediate VIII. Intermediate VIII (and later intermediates) may be obtained as a mixture of cis and trans isomers. Methods of controlling the stereochemical outcome of the above reactions are known to those skilled in the art of organic / pharmaceutical chemistry. Furthermore, methods for the separation of these isomers are known and detailed in the synthetic examples. If necessary, the group R ⁴ can be added by alkylation of intermediate VIII. Methods of controlling the absolute stereochemistry of the resulting asymmetric centers are well known to those skilled in the art as chiral separation methods. Ester hydrolysis, generally by heating with aqueous LiOH or an analogous base in the presence of an organic cosolvent such as THF, affords carboxylic acids IX. Treatment of acid IX with amine X under standard coupling conditions gives compound I of the invention. For a recent review of peptide coupling methods, see Ayman El-Faham and Fernando Albericio. Chem. Rev. 2011, 111, 6557-6602.

Piperidine and pyrrolidine ester XI are known compounds, undergo heteroaryl halide and S _N Ar reaction of general structure XII, to provide intermediate XIII (Y = N). These intermediates can be converted to the compounds of the present invention as described herein.

Scheme 3 describes a method of controlling the absolute stereochemistry of intermediate XIX and materials derived therefrom. Saponification of ester XIV gives carboxylic acid XV. Treatment of these acids with acid chlorides such as pivaloyl chloride gives mixed anhydride intermediates. In a separate reactor, an optically pure oxazolidinone of general structure XVI of known conformation is deprotonated by treatment with a strong base such as n-BuLi. These activators are combined to form acyl oxazolidinone XVII, which is deprotonated by a base such as NaHMDS. The alkylation of the resulting enolate proceeds under predictable stereochemical control at the newly formed center to give substance XVIII. Removal of the chiral auxiliary to obtain optically active carboxylic acid XIX is achieved by treatment with a solution of basic hydrogen peroxide. The history and scope of this reaction can be found in the review of DA Evans, MD Ennis, DJ Mathre. J. Am. Chem. Soc., 1982, 104 (6), pp 1737-1739. Compounds of general structure XIX can be converted to compounds of the invention by the methods described herein.

  The following examples provide those skilled in the art with a complete disclosure and description of how to practice and use the present invention and are intended to limit the scope of what the inventor regards as the invention. It does not mean that the following experiments have been conducted or that all experiments can be conducted. Although the description of the examples described in the present form is not necessarily implemented, it is to be understood that the description can be implemented to generate data of the nature described herein. Although the numbers used (e.g. amounts, temperatures etc) are accurate, it should be taken into account that there are some experimental errors and deviations.

  Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade (° C.), and pressure is at or near atmospheric pressure. Use standard abbreviations, including: wt = wild type; bp = base pair; kb = kilobase; nt = nucleotide; aa = amino acid; s or sec = second; min = minute; h or hr = hour; ng = nanogram; μg = microgram; Milligrams; g = grams; kg = kilograms; dl or dL = deciliters; μl or μL = microliters; ml or mL = milliliters; 1 or L = liters; μM = micromolar concentration; mM = millimolar concentration; M = molar concentration ; Im = intramuscular; ip = intraperitoneal; SC or SQ = subcutaneous; QD = daily; BID = twice daily; QW = weekly; QM = monthly; HPLC = fast Liquid chromatography; BW = body weight; U = unit; ns = statistical non-significant; PBS = phosphate buffered saline; IHC = immunohistochemistry; DMEM = Dulbecco's modified Eagle's medium; acid.

Analytical HPLC / MS was performed using the following method.
Method A: Column: Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: Water: 0.1% trifluoroacetic acid in water; temperature: 50 ° C .; gradient: 0 to 100% B over 3 minutes, then maintained at 100% B for 0.75 minutes; flow rate: 1.0 mL / min; detection: 220 nm UV.
Method B: Waters Acquity SDS using the following method: linear gradient from 2% to 98% solvent B over 1.7 minutes; UV visualization at 220 nm; column: BEH C18 2.1 mm × 50 mm; 1.7 μm particles Mobile phase A: 100% water, 0.05% TFA; Mobile phase B: 100% acetonitrile, 0.05% TFA.
Method C: Column: Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water containing 10 mM ammonium acetate; mobile phase B: 95: 5 acetonitrile: containing 10 mM ammonium acetate Water: temperature: 50 ° C .; gradient: 0 to 100% B over 3 minutes, then 100% B maintained for 0.75 minutes; flow rate: 1.0 mL / min; detection: 220 nm UV.

Intermediate product A
MTBE of 1,4-dioxaspiro [4.5] decan-8-one (300 g, 1920.86 mmol, 1.0 equivalent) and phenyl trifluoromethanesulfonimide (823.47 g, 2305.03 mmol, 1.2 equivalent) in MTBE ( A solution of 2.0 M NaHMDS in THF (1152.2 mL, 2305.03 mmol, 1.2 eq) is added to the solution at −78 ° C. under N ₂ over 70 minutes and the mixture is stirred for a further 60 minutes did. The reaction mixture was allowed to warm to room temperature and stirred overnight until TLC showed complete consumption of starting material. The mixture was quenched with aqueous KHSO ₄ (100 ml), filtered to remove solids, and the filtrate was concentrated completely. To the residue 3 L MTBE was added and washed with 5% NaOH (1.5 L x 3). The organic phase was concentrated to give 567 g crude product A (pale yellow oil, 102% yield). The crude can be used directly in the next step without further purification.
Product A: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 5.65 (t, J = 4.0 Hz, 1 H), 3.98 (d, J = 1.5 Hz, 4 H), 2.53 (s, 2 H), 2.40 (s, 2H), 1.90 (t, J = 6.6 Hz, 2H)

Product B
Crude product A (600 g, 2.08 mol, 1 equivalent), B ₂ Pin ₂ (687.1 g, 2.71 mol, 1.3 equivalents), KOAc (613 g, 6.24 mol, 3 equivalents), NaBr (86 g, 0.833Mol, 0.4 eq) and _{Pd (dppf) Cl 2 (76g} , 0.1mol, 0.05 a mixture of dioxane (6.5 L) eq) overnight, and heated to reflux. Once the reaction was complete, the mixture was concentrated and purified by FCC (2% → 10% → 20% EtOAc / PE) to give product B (369 g, 66%).
Product B: LC-MS: 267.1 (M + 1) +, ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.46 (s, 1 H), 3.98 (s, 4 H), 2.37-2.35 (m, 4 H), 1.74-1.60 (t, 2H), 1.24 (s, 12H)

Product C
Product B (368 g, 1.38 mol, 1.3 equiv), 4-chloro-6-fluoro-quinoline (195 g, 1.07 mol, 1 _{eq), K 2 CO 3 (445g} , 3.22mol, 3 equiv) and _{pd (PPh 3) 4 (25g} , 22mmol, 0.02 eq) in dioxane - water: a mixture of (3L, 4 1) in overnight and heated to reflux. The solution was concentrated and extracted with EtOAc. Purification with FCC (38% EtOAc / petroleum ether) gave product C (236 g, 77%).
Product C: LC-MS: 286.1 (M + 1) +, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80-8.29 (d, 1 H), 8.11-8.07 (q, 1 H), 7.63-7.61 (q , 1H), 7.47-7.46 (q, 1H), 7.26-7.22 (m, 1H), 5.75-5.74 (m, 1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H), 2.59 -2.53 (m, 2 H), 2.0-1. 97 (m, 2 H)

Product D
To product C (125 g, 0.44 mol) in IPA (2 L) was added 10% Pd / C at 55 ° C. and the mixture was stirred overnight under H ₂ atmosphere. The mixture was filtered and concentrated to give crude product D (130 g), which was used directly in the next step.

Product E
Product D (100 g, 0.348 mol) was treated with 4N HCl (300 mL) in acetone (1200 mL) at 45 ° C. overnight. The mixture was monitored by TLC. The solution was then concentrated under reduced pressure. The residue was adjusted to pH 9 with 6N NaOH and the mixture was partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a pale yellow solid which is used with hexane and ethyl acetate (20% ethyl acetate to 70% ethyl acetate) On a column of silica gel to give product E as a white solid (47 g + 20 g, mixture, yield> 55%). Product E: LC-MS: 244.0 (M + 1) +, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (d, J = 4.6 Hz, 1 H), 8.16 (dd, J = 9.3, 5.7 Hz, 1H), 7.72 (dd, J = 10.3, 2.8 Hz, 1H), 7.52 (ddd, J = 9.2, 7.8, 2.7 Hz, 1H), 7.29 (d, J = 4.6 Hz, 1H), 3.69 (ddd, J = 12.1, 9.0, 3.3 Hz, 1H), 2.77-2.54 (m, 4H), 2.37 (ddd, J = 13.4, 5.9, 3.0 Hz, 2H), 2.04 (qd, J = 12.6, 5.3 Hz, 2H)

Product F
Product E (57.8 g, 237.8 mmol) was dissolved in EtOH (240 mL) and cooled to 0.degree. NaBH ₄ (9.94 g, 261.6 mmol) was added in small portions, maintaining the temperature in the range of 0-10 ° C. (exothermic reaction). The resulting suspension was stirred for 20 minutes. LC / MS of an aliquot of the reaction mixture indicated the consumption of ketone (m / z (M + H) ⁺ = 244). The reaction was quenched at 0 ° C. by the slow addition of acetone (58 mL) over 15 minutes (exothermic reaction). The reaction was poured slowly into 500 mL of saturated aqueous ammonium chloride solution and 500 g of ice. The resulting aqueous solution was extracted with EtOAc (3 × 300 mL) and the combined organic fractions were washed with saturated aqueous ammonium chloride solution (250 mL) and saturated aqueous sodium chloride solution (250 mL). The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Enough silica for oil adsorption was added and diluted with 10% MeOH in CH ₂ Cl ₂ solution. An equivalent amount of silica was used as a silica plug for purification of the material. The silica plug was washed with 10% MeOH in CH ₂ Cl ₂ until no UV active was detected by TLC (7: 3 EtOAc / Hex, Rf = 0.4). The filtrate is concentrated, suspended in 500 mL of toluene and reconcentrated. The crude product F was isolated as a yellow solid (58.2 g) which was used in the next step without further purification.

Product G
To product F (58.2 g, 237.8 mmol), MeCN (125 mL) and pyridine (38.7 mL, 480 mmol) were added and the reaction mixture was cooled to 5 ° C. using an ice / water bath. Methanesulfonyl chloride (26.0 mL, 336 mmol) was added dropwise at 5 ° C. (exothermic reaction) and the reaction mixture was stirred for 1 hour at 5 ° C., brought to room temperature and stirred for a further 16 hours, during which a white precipitate formed . The heterogeneous mixture was quenched by the addition of saturated aqueous ammonium chloride solution (200 mL) and extracted with CH ₂ Cl ₂ (3 × 300 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The excess pyridine was removed azeotropically with toluene (3 × 300 mL). The crude material was recrystallized from H ₂ O / MeOH as follows. 1 mL / mmol H ₂ O was added and the slurry was heated at 120 ° C. in an oil bath. MeOH was added until the solid went into solution (about 0.5 L). After cooling, the white crystals were separated by filtration to give product G (58.6 g,> 20: 1 dr, 76% over 2 steps). m / z (M + H) ⁺ = 324.1 ¹ H NMR (400 MHz; CDCl ₃ ): δ 8.82 (dd, J = 4.6, 0.2 Hz, 1 H), 8.15-8.11 (m, 1 H), 7.64-7.61 (m, 1 H), 7.52-7.46 (m, 1 H), 7. 25 (s, 1 H), 4. 78 (tt, J = 10.9, 5.2 Hz, 1 H), 3.24-3.16 (m, 1 H), 3.07 (d, J = 1.0 Hz, 3H), 2.42-2.38 (m, 2H), 2.16-2.12 (m, 2H), 1.93-1.66 (m, 4H)

Product H
Di-tert-butyl malonate (33.5 mL, 150 mmol) is cooled in a water-ice bath and under stirring Ar, 1,2-dimethoxyethane (100 mL) in NaH (6.0 g, 60 in oil) % Suspension, 150 mmol) was added dropwise to the suspension. After stirring for 10 minutes, product G (16.2 g, 50 mmol) was added and the reaction was heated at 85 ° C. for 20 hours. After this, acetic acid (100 mL) was added, the reaction flask was equipped with a distillation head, and the temperature was raised to 130.degree. The 1,2-dimethoxyethane is distilled off at atmospheric pressure until the distillate is acidic (about 100 mL). Remove the distillation head, install a reflux condenser, add water (20 mL) and heat the reaction at 130 ° C. for 12 hours. The reaction was concentrated under reduced pressure and poured into 200 g of ice and 100 mL of saturated aqueous NaOAc solution. Product H was isolated by filtration as a white solid and further dried by refluxing with toluene in a Dean-Stark apparatus (11.0 g, 76%). m / z (M + H) ⁺ = 288.2. ¹ H NMR (400 MHz; DMSO-d ₆ ): δ 12.05 (bs, 1 H), 8.79 (d, J = 4.5 Hz, 1 H), 8.06 (dd, J = 9.2, 5.8 Hz, 1 H), 7. 94 (dd, J = 11.0, 2.8 Hz, 1 H), 7. 66-7.61 (m, 1 H), 7. 50 (d, J = 4.6 Hz, 1 H), 2.41 (d, J = 7.6 Hz, 2H), 2.28-2.23 (m, 1H), 1.87-1.78 (m, 2H), 1.73-1.64 (m, 6H)

Product I
Product H (1.4 g, 4.8 mmol) in THF (15 mL) solution of was added NEt ₃ (1.3mL, 9.6mmol). The reaction mixture was cooled to 0 ° C., trimethylacetyl chloride (0.713 mL, 5.8 mmol) was added dropwise and the resulting solution was stirred at 0 ° C. for 30 minutes. In a separate flask, a solution of (R) -4-phenyloxazolidin-2-one (3, 1.01 g, 6.24 mmol) in THF (45 mL) at 0 ° C. in 1 M LiHMDS in THF (6.24 mL, 6 Treated with .24 mmol dropwise) and stirred at 0.degree. The lithium was added to the first flask via cannula. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution (50 mL) and the layers separated. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts are dried over anhydrous sodium sulfate and chromatographed on silica using an EtOAc / hexane 0-100% gradient to give product I as a white foam in 83% yield The m / z (M + H) ⁺ = 433.3. ¹ H NMR (400 MHz; CDCl ₃ ): δ 8.80 (d, J = 4.5 Hz, 1 H), 8.11 (dd, J = 9.1, 5.7 Hz, 1 H), 7.63 (dd, J = 10.5, 2.5 Hz, 1 H), 7.48-7.43 (m, 1 H), 7.40-7.30 (m, 6 H), 5.47-5.44 (m, 1 H), 4.71 (t, J = 8.9 Hz, 1H), 4.31-4.28 (m, 1H), 3.20-3.11 (m, 3H), 2.49-2.46 (m, 1H), 1.82-1.67 (m, 6H)

Product J
A solution of product I (21.6 g, 50 mmol) in anhydrous THF (200 mL) is cooled to -40 ° C. (using acetonitrile / dry ice bath, a slight precipitation occurs), and a 2 M solution of NaHMDS in THF (30 mL, 60 mmol) Added over 5 minutes (5-8 ° C. temperature increase observed). The resulting yellow reaction mixture was stirred for 10 minutes, becoming homogeneous, and MeI (10.6 g, 75 mmol) was added over 2 minutes (a 10 ° C. temperature rise was observed). The reaction mixture is stirred for 1 hour at -40 ° C and LC / MS shows complete consumption of starting material and formation of the desired methyl imide. The reaction mixture was rapidly diluted with saturated aqueous ammonium chloride solution (400 mL) and the biphasic mixture was stirred for 15 minutes. ⁱ added PrOAc the (100 mL), the layers separated, the aqueous layer was extracted with ⁱ PrOAc (3 × 50mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in 400 mL hot acetone and recrystallized by adding H ₂ O until a milky solution was formed, then redissolved with heating (about 3: 1 acetone / H ₂ O). Product J was obtained as white needles (15.04 g, 2 portions, 68%). m / z (M + H) ⁺ = 447.3. ¹ H NMR (400 MHz; CDCl ₃ ): δ 8.81 (d, J = 4.6 Hz, 1 H), 8. 10 (dd, J = 9.2, 5.7 Hz, 1 H), 7.56 (dd, J = 10.6, 2.7 Hz, 1 H), 7.47-7.42 (m, 1 H), 7.41-7.29 (m, 6 H), 5. 47 (dd, J = 8.8, 3.8 Hz, 1 H), 4.69 (t, J = 8.9 Hz, 1 H), 4.38-4.30 (m, 1 H), 4.26 (dd, J = 8.9, 3.9 Hz, 1 H), 3.26-3.21 (m, 1 H), 2.18-2.15 (m, 1 H), 1.93 -1.64 (m, 8H), 1.09 (d, J = 6.9 Hz, 3H)

Product K
A solution of product J (82.0 g, 183.6 mmol) in THF (610 mL) at 0 ° C. in H ₂ O ₂ aqueous solution (35 wt%, 82 mL) and LiOH (7.04 g, 293.8 mmol) in H ₂ O (189 mL) solution was added. The resulting reaction mixture was slowly warmed to rt and stirred overnight. The reaction was cooled to 0 ° C. and saturated aqueous sodium bisulfite solution (250 mL) was added. After stirring for 30 minutes, THF was removed under reduced pressure. Acetic acid (34 mL) was added followed by EtOAc (300 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 500 mL). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The brown crude reaction mixture was suspended in MeCN (400 mL) and the suspension was refluxed with vigorous stirring. After cooling to rt, the solid was collected by filtration and washed with more MeCN. Product K was obtained as a white solid (45.4 g, 82%). m / z (M + H) ⁺ = 302.2. ¹ H NMR (400 MHz; DMSO-d6): δ 12.10 (s, 1 H), 8.79 (d, J = 4.5 Hz, 1 H), 8.07 (dd, J = 9.2, 5.9 Hz, 1H), 7.97-7.94 (m, 1H), 7.67-7.62 (m, 1H), 7.49 (d, J = 4.5 Hz, 1H), 3.41-3.36 (m, 1H), 2.73-2.65 (m, 1 H), 1. 83-1.6 1 (m, 9 H), 1.0 8 (d, J = 6.8 Hz, 3 H). Chiral HPLC,> 99% ee (Chiralpak IC-3, 3 μM, 4.6 × 250 mm, 15 min. Composition 70% heptane 30% detection at 230 nm i-PrOH): 0.75 mL / min flow rate, desired enantiomer retention time 8.6 minutes, unnecessary enantiomer retention time 9.5 minutes

Example 1
N- (4-Chloro-2-methylbenzyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide
1A. Methyl 2- (4-methylpiperidin-4-yl) acetate To a flask charged with MeOH (7.5 mL) was slowly added acetyl chloride (1.1 mL, 15.2 mmol) at 0 ° C. under a nitrogen atmosphere . After the addition is complete, the mixture is stirred for 5 minutes at 0 ° C. to give a homogeneous mixture of 2- (4-methylpiperidin-4-yl) acetic acid, HCl (675.0 mg, 3.5 mmol) in MeOH (1.5 mL). It dripped slowly. The resulting homogeneous mixture is stirred at 0 ° C. for 5 minutes and then at 60 ° C. for 8 hours and concentrated under reduced pressure to give the HCl salt of the title compound as a white solid (718.0 mg; 99% yield), Was used without further purification. MS (ES): m / z = 172 [M + H] ⁺ .t _R = 0.46 min (Method B). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41-9.12 (m, 1 H), 3.60 (s, 3H), 3.25-3.15 (m, 2H), 2.93-2.82 (m, 2H), 2.39-2.30 (m, 2H), 1.74-1.64 (m, 4H), 1.02 (s, 3H)

1-B. Methyl 2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetate 4-chloro-6-fluoroquinoline (350.0 mg, 1.9 mmol) in a closed vial To a homogeneous mixture of anhydrous NMP (5 mL), HCl salt of methyl 2- (4-methylpiperidin-4-yl) acetate (1A, 480.0 mg, 2.3 mmol) followed by DIPEA (1.6 mL, 2 mmol) were added. The vial was sealed and the mixture was stirred at 120 ° C. After 26 h, the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The organic layers were combined, washed with brine and concentrated under reduced pressure to give a crude product. Purification by Isco chromatography gave methyl 2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetate as an oil (565.8 mg; 93% yield) ) MS (ES): m / z = 317 [M + H] ⁺ .t _R = 0.66 min (Method B). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (d, J = 5.4 Hz) , 1H), 7.96 (dd, J = 11.7, 2.8 Hz, 1H), 7.89-7.84 (m, 1H), 7.55-7.49 (m, 1H), 6.54 (d, J = 5.5 Hz, 1H), 3.82- 3.63 (m, 2H), 3.59 (s, 3H), 3.54-3.34 (m, 2H), 2.45-2.38 (m, 2H), 1.87-1.72 (m, 4H), 1.05 (s, 3H)

1C. 2- (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetic acid methyl 2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidine- To a homogenous mixture of 4-yl) acetate (321.0 mg, 1.0 mmol) in MeOH (5 mL) was added dropwise 2 M aqueous NaOH solution (1 mL, 2.0 mmol) under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 20 hours and treated with 1N HCl (aq) until pH 5-6 with pH paper. The mixture was partitioned between water and EtOAc, the layers separated, and the aqueous layer extracted twice with EtOAc. The aqueous layer from the extract was lyophilized to afford the HCl salt of the crude product as an off-white solid (312.1 mg, 91% yield), which was used without further purification. MS (ES): m / z = 303 [M + H] ⁺ .t _R = 0.59 min (Method B). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (br.s, 1 H), 8.41 (d, J = 6.1 Hz, 1 H), 8.12 (dd, J = 11.5, 2.7 Hz, 1 H), 8.04-7.94 (m, 1 H), 7.75-7.64 (m, 1 H), 6.64 (d, J = 6.2 Hz, 1H), 3.98-3.87 (m, 1H), 3.87-3.78 (m, 1H), 3.69-3.49 (m, 2H), 2.38-2.29 (m, 2H), 1.92-1.70 (m, 4H), 1.06 (s, 3H)

Example 1. N- (4-Chloro-2-methylbenzyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide 2- (1- (6) -Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetic acid HCl salt (1C, 25.6 mg, 0.09 mmol) and 4-chloro-2-methylbenzylamine (15.8 mg, 0. 1). To a mixture of 1 mmol) in anhydrous DMF (1 mL) was added DIPEA (0.05 mL, 0.3 mmol) followed by PyBOP (44.1 mg, 0.09 mmol) under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 156 hours, diluted with DMF, filtered through a syringe filter and purified by preparative HPLC / MS to give the title compound (22.2 mg; 60% yield). MS (ES): m / z = 440 [M + H] ⁺ .t _R = 1.52 min (Method A). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.37-8.30 (m, 2 H), 7.99 -7. 92 (m, 1 H), 7. 85 (dd, J = 9.1, 6.1 Hz, 1 H), 7.58-7.49 (m, 1 H), 7.24-7.13 (m, 3 H), 6.51 (d, J = 5.6 Hz, 1 H) ), 4.17 (d, J = 5.5 Hz, 2H), 3.80-3.60 (m, 2H), 3.54-3.32 (m, 2H), 2.26-2.19 (m, 5H), 1.84-1.67 (m, 4H), 1.02 (s, 3H)

Examples 2 to 5
The compounds of Examples 2 to 5 are treated with 2- (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetic acid (1C) and the corresponding amines in Example 1 The compound was prepared according to the method described for the synthesis of the compound of

Example 6
(S) -2- (4-Methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) -N- (1-phenylpropyl) acetamide
The title compound (28.0 mg), 4-chloro-2- (trifluoromethyl) pyridine (300.0 mg, 1.7 mmol) is used in place of 4-chloro-6-fluoroquinoline, (S) -1 Prepared according to the synthesis of the compound of Example 1 except that phenylpropan-1-amine (14 mg, 0.104 mmol) was used instead of 4-chloro-2-methylbenzylamine. MS (ES): m / z = 420 [M + H] ⁺ .t _R = 1.36 min (Method A). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.28 (d, J = 8.2 Hz, 1 H , 8.17 (t, J = 6.3 Hz, 1H), 7.33-7.25 (m, 4H), 7.22-7.17 (m, 1H), 6.76 (s, 1H), 6.65-6.48 (m, 1H), 4.71- 4.61 (m, 1H), 3.50-3.34 (m, 2H), 3.14-3.01 (m, 2H), 2.30-2.11 (m, 2H), 1.84-1.69 (m, 2H), 1.69-1.59 (m, 4H) ), 1.00 (s, 3H), 0.84-0.78 (m, 3H)

Examples 7-9
The compounds of Examples 7-9 are treated with 2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetic acid and the corresponding amines. Prepared according to the method described for the synthesis of compound 6.

Example 10
(R) -N- (2-chlorobenzyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide
Example 10: (R) -N- (2-chlorobenzyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide Preparation K (see above) (20 mg, 0.066 mmol) was dissolved in thionyl chloride (48.4 μl, 0.664 mmol) and DMF (2.57 μl, 0.033 mmol) was added. The reaction was stirred at room temperature. After 1 h, the reaction was concentrated under reduced pressure, dissolved in toluene, reconcentrated and subjected to high vacuum to remove excess thionyl chloride. After 15 minutes, the crude acyl chloride is dissolved in ACN (664 μl) and a solution of (2-chlorophenyl) methanamine (18.79 mg, 0.133 mmol) in ACN (664 μl) and TEA (46.3 μl, 0.332 mmol) is added. Added at ° C. After 16 h, the reaction was concentrated under reduced pressure, dissolved in DMF (2 mL), filtered and purified by HPLC to give the compound of Example 10 (26.4, 0.062 mmol, 94% yield ). _{LC-MS C 25 H 26 ClFN} 2 O Analysis Calculated 424.17, Found _{[M + H] 425.2 T r} = 0.78 min (method ^{B) 1 H NMR (500 MHz} , DMSO-d 6) δ:. 8.82 ( d, J = 4.5 Hz, 1 H), 8. 48 (t, J = 5.3 Hz, 1 H), 8.08 (dd, J = 9.0, 5.8 Hz, 1 H), 7. 96 (dd, J = 10.9, 2.3 Hz, 1 H), 7.61-7.69 (m, 1 H), 7.52 (d, J = 4.5 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.20-7.36 (m, 3 H), 4.27-4.42 (m, 2 H) , 3.36 (br. S., 1H), 2.77 (dd, J = 10.8, 6.7 Hz, 1H), 1.80-1.98 (m, 3H), 1.50-1.80 (m, 6H), 1.06 (d, J = 6.6) Hz, 3H)

Examples 11 to 18
The compounds of Examples 11-18 were prepared using the method of preparing the compound of Example 10 from Product K and the corresponding benzylamine.

Analytical HPLC / MS was performed using the following method for Examples 19-24: Method A: Waters Acquity SDS using the following method: linear gradient from 2% to 98% solvent B over 1.7 minutes UV visualization at 220 nm; column: BEH C18 2.1 mm × 50 mm; 1.7 μm particles (heated to a temperature of 50 ° C.) flow rate: 0.8 ml / min; mobile phase A: 100% water, 0.05% Mobile phase B: 100% acetonitrile, 0.05% TFA.
Method B: Column: Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: Water: 0.1% trifluoroacetic acid-containing water; temperature: 50 ° C .; gradient: 0 to 100% B over 3 minutes, then maintained at 100% B for 0.75 minutes; flow rate: 1.00 mL / min; detection: 220 nm UV.
Method C: Column: Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm particles; mobile phase A: 5: 95 acetonitrile: water with 0.1% trifluoroacetic acid; mobile phase B: 95: 5 acetonitrile: Water: 0.1% trifluoroacetic acid in water; temperature: 50 ° C .; gradient: 0 to 100% B over 3 minutes, then maintained at 100% B for 0.75 minutes; flow rate: 1.0 mL / min; detection: 220 nm UV.

Example 19-1
N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide (Enantiomer 1, absolute stereochemistry determined Not)
And Example 19-2
N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide (enantiomer 2, never by absolute stereochemistry Not in)

19A. Tert-Butyl 4- (6-fluoroquinolin-4-yl) piperazine-1-carboxylate, anhydrous NMP (5 mL) of 4-chloro-6-fluoroquinoline (500.0 mg, 2.8 mmol) in a closed vial To the mixture of 1-Boc-piperazine (750.0 mg, 4.0 mmol) was added followed by DIPEA (2.0 mL, 11.5 mmol). The vial was closed and the mixture was stirred at 120 ° C. for 15.5 hours. The reaction mixture was cooled to room temperature and partitioned between water and Et 2 _O. The layers were separated and the aqueous layer was extracted twice more with Et ₂ O. These organic extracts were combined with the original organic layer, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a crude product. Purification by Isco chromatography gave tert-butyl 4- (6-fluoroquinolin-4-yl) piperazine-1-carboxylate as an oil (719.3 mg; 77% yield). MS (ES): m / z = 332 [M + H] ⁺ .t _R = 0.70 min (Method A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (d, J = 4.9 Hz, 1 H ), 8.09-8.00 (m, 1H), 7.77-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.07 (d, J = 4.9 Hz, 1H), 3.67-3.57 (m, 4H), 3.15-3.06 (m, 4H), 1.44 (s, 9H)

19B. 6-Fluoro-4- (piperazin-1-yl) quinoline tert-butyl 4- (6-fluoroquinolin-4-yl) piperazine-1-carboxylate (600.0 mg, 1.8 mmol) in dioxane (4 mL) To a homogeneous mixture in) was added 4M HCl in dioxane (10 mL, 40.0 mmol) under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 2.5 hours, during which time a precipitate formed. The heterogeneous mixture was concentrated to about 1/2 of the original volume. Vacuum filtration gave the HCl salt of the title compound as an off-white solid (490.0 mg; 100% yield), which was used without further purification. MS (ES): m / z = 232 [M + H] ⁺ . T _R = 0.38 min (Method A)

19C. (±) -Ethyl 2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanoate Sealable reaction vial of 6-fluoro-4- (piperazin-1-yl) quinoline HCl salt (19B, 200.0mg, 0.75mmol) in heterogeneous mixture of anhydrous DMF (5 mL) _{of, K 2 CO 3 (288.0mg,} 2.08mmol), followed by ethyl 2-bromo-valerate (234 .0 mg, 1.12 mmol) were added. The flask was sealed and the mixture was stirred at 60.degree. After 16 h, the reaction was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The organic layers are combined, washed with brine, dried (anhydrous Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the product as a yellow oil which is used in the next step without further purification did. MS (ES): m / z = 360 [M + H] ⁺ . T _R = 0.62 min (Method A)

19D. (±) -2- (4- (6-Fluoroquinolin-4-yl) piperazin-1-yl) ethyl 2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl ethyl pentanoate ) 2M NaOH (aq) (0.8 mL, 1.6 mmol) was added dropwise to a homogenous mixture of pentanoate (19C, 0.75 mmol) in MeOH (4 mL) under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 64 hours and 2M NaOH (aq) (0.8 mL, 1.6 mmol) was added. After stirring for 6 h, 2 M NaOH (aq) (0.8 mL, 1.6 mmol) was added and stirring was continued. After 115 h, the reaction was treated with HCl (4 N dioxane) until pH 5 with pH paper. The mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was lyophilized to give a pale yellow solid. RP preparative HPLC (YMC-ODS 5μ 250 × 30 column. Conditions: 30 mL / min flow rate; 30 to 100% B 30 to 100% B 40 min gradient (solvent A = 95: 5 H ₂ O / 0.05% TFA) Containing MeCN (solvent B = 5: 95 H ₂ O / 0.05% TFA MeCN), purification of 2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanoic acid The TFA salt was obtained as a pale yellow solid (160.0 mg; 58% yield) MS (ES): m / z = 332 [M + H] ⁺ .t _R = 0.46 min (method A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (d, J = 6.4 Hz, 1 H), 8. 10 (dd, J = 10.1, 5.2 Hz, 1 H), 7.93-7.86 (m, 2 H), 7.28 (d, J = 6.5 Hz, 1H), 3.84-3.73 (m, 4H), 3.72-3.51 (m, 1H), 3.38-2.99 (m, 4H), 1.86-1.68 (m, 2H), 1.46-1.33 (m, 2H) ), 0.94 (t, J = 7.3 Hz, 3H)

19E. (±) -N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide in a sealed vial , (±) -2- (4- (6-Fluoroquinolin-4-yl) piperazin-1-yl) pentanoic acid (19D, 32.0 mg, 0.10 mmol) in anhydrous DMF (1.5 mL) To the solution was added PyBOP (50.3 mg, 0.10 mmol) followed by DIPEA (0.06 mL, 0.34 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes and (3s, 5s, 7s) -adamantan-1-amine (17.5 mg, 0.12 mmol) was added. The vial was sealed and the reaction was stirred at ambient temperature for 63 hours, diluted with DMF, passed through a syringe filter, and purified by preparative HPLC / MS to give the title compound as a racemate (10.3 mg; 23 %yield). MS (ES): m / z = 465 [M + H] ⁺ . T _R = 1.36 min (Method B)

Example 19-1. N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide (Enantiomer 1) , Absolute stereochemistry not determined)
And Example 19-2. N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide (enantiomers) 2, absolute stereochemistry not determined)
Racemic compound 19E (10.3 mg) was purified by chiral SFC (MeOH mobile phase containing 80/20 CO ₂ /0.1% DEA, chiral AD 25 × 3 cm, 5 μm column, 85 ml / min, detector wavelength = 220 nm ). Upon concentration of the appropriate fractions (previously eluted), the compound of Example 19-1 (4.7 mg) was N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6) -Fluoroquinolin-4-yl) piperazin-1-yl) pentanamide (Enantiomer 1). MS (ES):.. M / z = 465 [M + H] + T r = 1.53 min (method ^{B) 1 H NMR (500 MHz} , DMSO-d 6) δ 8.63 (d, J = 4.9 Hz, 1H 8.00 (dd, J = 9.0, 5.6 Hz, 1 H), 7.64-7.53 (m, 2 H), 7.41 (s, 1 H), 7.02 (d, J = 4.9 Hz, 1 H), 3.19-3.03 (m, 4H), 2.97 (dd, J = 8.8, 5.2 Hz, 1H), 2.85-2.69 (m, 4H), 2.00-1.91 (m, 9H), 1.62-1.56 (m, 7H), 1.50-1.41 (m, 1H), 1.28-1.19 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H)

Concentration of the other fraction (later elution) gave the compound of Example 19-2 (4.9 mg) as N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6). MS (ES): m / z = 465 [M + H] ⁺ .T _r = 1.53 min (Method B) -Fluoroquinolin-4-yl) piperazin-1-yl) pentanamide (Enantiomer 2). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.65 (d, J = 4.7 Hz, 1 H), 8.04-7.98 (m, 1 H), 7.64-7.53 (m, 2 H), 7.39 (s, 1 H), 7.02 (d, J = 4.6 Hz, 1 H), 3.20-3.01 (m, 4 H), 2. 98 (dd, J = 8.2, 5.2 Hz, 1 H), 2.85-2.69 (m, 4 H), 2.02-1.92 (m, 9H), 1.64-1.56 (m, 7H), 1.50-1.41 (m, 1H), 1.28-1.21 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H)

Example 20-1
N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide (Enantiomer 1, absolute stereochemistry is determined Absent)
And Example 20-2
N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide (Enantiomer 2, absolute stereochemistry is determined Absent)

20A. Tert-Butyl 4- (1-ethoxy-1-oxobutan-2-ylidene) piperidine-1-carboxylate NaH (0.29 g, 7.18 mmol) in anhydrous THF (10 mL) suspension under nitrogen atmosphere , Triethyl 2-phosphonobulate (1.81 g, 7.18 mmol) was added over 5 minutes. The resulting mixture was stirred at ambient temperature for 20 minutes, during which time it became homogeneous. To this solution was added a homogenous mixture of 1-Boc-4-piperidone (1.10 g, 5.52 mmol) in anhydrous THF (2.5 mL). After stirring for 1.5 h, the reaction was quenched with saturated NH ₄ Cl (aq) solution and extracted well with EtOAc. The organic fractions are combined, washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give tert-butyl 4- (1-ethoxy-1-oxobutan-2-ylidene) piperidine-1-carboxylate Was obtained as a clear oil (1.64 g; 100% yield) and used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.13 (q, J = 7.1 Hz, 2 H), 3.39-3.35 (m, 2 H), 3.35-3.31 (m, 2 H), 2.45-2.39 (m, 2 H) ), 2.31-2.22 (m, 4H), 1.40 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H)

20B. (±) -tert-Butyl 4- (1-ethoxy-1-oxobutan-2-yl) piperidine-1-carboxylate tert-butyl 4- (1-ethoxy-1-oxobutan-2-ylidene) piperidine To a flask charged with 1-carboxylate (1.64 g, 5.52 mmol) was carefully added platinum (IV) oxide (0.07 g, 0.31 mmol) followed by EtOH (5 mL) under a nitrogen atmosphere. The nitrogen line was changed to a hydrogen balloon and the mixture was stirred at ambient temperature. After 15 h, the reaction mixture was purged with nitrogen and filtered through a pad of celite. The pad was rinsed thoroughly with EtOAc and the combined filtrate was concentrated under reduced pressure to give racemic tert-butyl 4- (1-ethoxy-1-oxobutan-2-yl) piperidine-1-carboxylate as a clear solution ( 1.65 g; 100% yield), which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.08 (q, J = 7.1 Hz, 2 H), 3.98-3.83 (m, 2 H), 2.78-2.52 (m, 2 H), 2.13-2.03 (m, 1 H) ), 1.69-1.62 (m, 1H), 1.52-1.43 (m, 2H), 1.38 (s, 9H), 1.28-1.13 (m, 5H), 1.10-0.98 (m, 2H), 0.80 (t, J) = 7.3 Hz, 3H)

20C. (±) -Ethyl 2- (piperidin-4-yl) butanoate tert-butyl 4- (1-ethoxy-1-oxobutan-2-yl) piperidine-1-carboxylate (1.65 g, 5.52 mmol) HCI (4 N dioxane, 10 mL, 40.0 mmol) was added to a homogeneous mixture of in anhydrous dioxane (5 mL) under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 2 hours and concentrated under reduced pressure to remove volatiles. The resulting oil was treated with saturated aqueous NaHCO ₃ until pH 5, then with 1 N NaOH (aq) to pH 8, and the mixture was extracted thoroughly with EtOAc. The layers were separated and the aqueous layer was lyophilized to afford the HCl salt of the title compound as a pale yellow solid (1.20 g; 92% yield) which was used in the next step without further purification. MS (ES): m / z = 200 [M + H] ⁺ .t _R = 0.57 min (Method A). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.07 (q, J = 7.2 Hz, 2H ), 3.01-2.78 (m, 2H), 2.48-2.29 (m, 3H), 2.07-1.98 (m, 1H), 1.60-1.35 (m, 5H), 1.18 (t, J = 7.1 Hz, 3H), 1.11-0.88 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H)

20D. (±) -Ethyl 2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanoate ethyl 2- (piperidin-4-yl) butanoate, HCl ( To a homogenous mixture of 20 C, 187.0 mg, 0.8 mmol) in anhydrous DMF (3 mL) was added K ₂ CO ₃ (351.0 mg, 2.5 mmol). The mixture was stirred at ambient temperature for 5 minutes, 2- (chloromethyl) -6- (trifluoromethyl) pyridine (164.0 mg, 0.8 mmol) was added, the vial was sealed and the mixture was stirred at 40 ° C. . After stirring for 63 h, the mixture was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted twice more with EtOAc. The organic layers are combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title compound as a golden oil (265.4 mg; 83% yield), Used without further purification. MS (ES): m / z = 359 [M + H] ⁺ .t _R = 0.72 min (Method A). ¹ H NMR (400 MHz, DMSO-d6) d 8.05 (t, J = 7.8 Hz, 1 H) , 7.79-7.70 (m, 2H), 4.14-4.03 (m, 2H), 3.63 (s, 2H), 2.86-2.74 (m, 2H), 2.12-1.93 (m, 3H), 1.71-1.63 (m, 2) 1H), 1.59-1.40 (m, 4H), 1.29-1.14 (m, 5H), 0.80 (t, J = 7.4 Hz, 3H)

20 E. (±) -2- (1-((6- (Trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) ethyl 2-butanoate 2- (1-((6- (trifluoromethyl) )) Pyridin-2-yl) methyl) piperidin-4-yl) butanoate (265.4 mg, 0.7 mmol) in a homogeneous mixture of EtOH (3 mL) under an atmosphere of nitrogen, NaOH (8 M aqueous solution, 0.75 mL, 6 .0 mmol) was added. The mixture is stirred at 40 ° C. for 48 hours, then at room temperature for another 69 hours, quenched with 4N HCl in dioxane (2.0 mL, 8.0 mmol), stirred at room temperature for 10 minutes, concentrated under reduced pressure and crude The HCl salt of the product was obtained as a tan solid which was used in the next step without further purification. MS (ES): m / z = 331 [M + H] ⁺ . T _R = 0.60 min (Method A)

20F. (±) -N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide
HCl salt of (±) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanoic acid (20E, 30.0 mg, 0.07 mmol) anhydrous To the mixture in DMF was added PyBOP (57.6 mg, 0.1 mmol) followed by DIPEA (0.1 mL, 0.6 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes and 2-adamantanamine hydrochloride (18.0 mg, 0.1 mmol) was added. The vial was sealed and the reaction was stirred at ambient temperature for 24 hours, diluted with DMF, passed through a syringe filter and purified by preparative HPLC / MS to give the title compound as a racemate (17.0 mg; 48) %yield). MS (ES): m / z = 464 [M + H] ⁺ . T _R = 1.76 min (Method B)

Example 20-1. N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide (Enantiomer 1, absolute) Stereochemistry not determined)
And Example 20-2. N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide (Enantiomer 2, Absolute stereochemistry not determined)
Racemic compound 20F (14.8 mg) was purified by chiral SFC (MeOH mobile phase containing 81/19 CO ₂ /0.1% DEA, chiral AD 25 × 3 cm, 5 μm column, 85 ml / min, detector wavelength = 220 nm ). Upon concentration of the appropriate fractions (above), the compound of Example 20-1 (7.2 mg) was purified by N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridine- 2-yl) methyl) piperidin-4-yl) butanamide (Enantiomer 1). MS (ES):.. M / z = 464 [M + H] + T r = 1.78 min (method ^{B) 1 H NMR (500 MHz} , DMSO-d 6) δ 8.05 (t, J = 7.7 Hz, 1H ), 7.76 (d, J = 7.6 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7. 65 (d, J = 7.5 Hz, 1 H), 3.91-3.40 (m, 2 H), 2.91-2.67 (m, 2H), 2.11-1.88 (m, 5H), 1.81-1.64 (m, 11H), 1.48-1.10 (m, 8H), 0.75 (t, J = 7.2 Hz, 3H)

The compound of Example 20-2 (5.8 mg) was N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridine) by concentration of the other fractions (later elution). -2-yl) methyl) piperidin-4-yl) butanamide (Enantiomer 2). MS (ES):.. M / z = 464 [M + H] + T r = 1.74 min (method ^{B) 1 H NMR (500 MHz} , DMSO-d 6) δ 8.05 (t, J = 7.8 Hz, 1H ), 7.76 (d, J = 7.6 Hz, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.62 (d, J = 7.6 Hz, 1 H), 3.91-3.57 (m, 2 H), 2.88-2.70 (m, 2H), 2.13-1.89 (m, 5H), 1.82-1.65 (m, 11H), 1.50-1.15 (m, 8H), 0.76 (t, J = 7.2 Hz, 3H)

Example 21
(cis)-(2R) -N- (3,5-dimethyladamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide
(cis)-(R) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) propanoic acid (Product K, 0.030 g, 0.1 mmol) and 3,5-dimethyladamantane-1- Amine, a solution of HCl (0.024 g, 0.110 mmol) in DMF (0.4 mL) was treated with triethylamine (0.049 mL, 0.350 mmol) followed by HATU (0.046 g, 0.120 mmol). The resulting solution was stirred for 1 h at RT, quenched with 1 drop of water and purified by preparative HPLC. Concentration of the appropriate fractions gave (cis)-(2R) -N- (3,5-dimethyladamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide Obtained (0.042 g, 91% yield). MS (ES):.. M / z = 463 [M + H] + t R = 0.97 min (Method ^{A) 1 H NMR (400 MHz} , DMSO-d 6) δ 8.85 (d, 1H, J = 4.4 Hz , 8.09 (dd, 1 H, J = 9.0, 5.8 Hz), 7.96 (br. D, 1 H, J = 9.1 Hz), 7.63-7.69 (m, 1 H), 7.56 (d, 1 H, J = 4.2 Hz) , 7.42 (s, 1H), 3.30-3.37 (m, 1H), 2.58-2.65 (m, 1H), 2.05 (s, 1H), 1.87-1.96 (m, 1H), 1.52-1.83 (m, 14H) , 1.26 (ABq, 4H, J AB = 11.8 Hz, δν = 37.3 Hz), 1.08 (s, 2H), 0.96 (d, 3H, J = 6.5 Hz), 0.81 (s, 6H)

Example 22
N-((3s, 5s, 7s) -adamantan-1-yl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide
22A. 2- (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetic acid 4-chloro-6-fluoroquinoline (200.0 mg, 1.1 mmol) in a closed vial To a mixture in anhydrous NMP (4 mL) was added 2- (4-methylpiperidin-4-yl) acetic acid, HCl (320.0 mg, 1.7 mmol) followed by DIPEA (0.8 mL, 4.6 mmol) . The vial was sealed and the mixture was stirred at ambient temperature for 2 hours and then at 120 ° C. for 65 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted twice more with EtOAc. The product was determined to be mostly in the aqueous layer, followed by acidification with 6 M HCl (aq) (0.76 mL, 4.6 mmol) and lyophilization to give the crude product as an oil. Purification by Isco chromatography followed by preparative HPLC gave the HCl salt of the title compound as a clear residue (23.3 mg; 7% yield). MS (ES): m / z = 303 [M + H] ⁺ .t _R = 0.58 min (Method A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.84 (br. S., 1 H), 8.48 (d, J = 7.1 Hz, 1 H), 8.32 (d, J = 10.4 Hz, 1 H), 8.03-7.85 (m, 2 H), 6.77 (d, J = 7.2 Hz, 1 H), ~ 3.60 (m, Overlap, exact chemical shifts are water peak overlap unknown), 2.40-2.29 (m, 2H), 2.00-1.82 (m, 2H), 1.80-1.66 (m, 2H), 1.08 (s, 3H)

Example 22. N-((3s, 5s, 7s) -adamantan-1-yl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetic acid (22A, 21.0 mg, 0.07 mmol) and (3s, 5s, 7s) -adamantan-1-amine, To a mixture of HCl (15.7 mg, 0.08 mmol) in anhydrous DMF (1 mL) under a nitrogen atmosphere, add DIPEA (0.04 mL, 0.2 mmol) followed by PyBOP (36.1 mg, 0.07 mmol) did. After stirring for 7.5 days at ambient temperature, the mixture was diluted with DMF, filtered through a syringe filter, and purified by preparative HPLC / MS to give the title compound (17.9 mg; 59% yield). MS (ES): m / z = 436 [M + H] ⁺ .t _R = 1.67 min (Method B). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.34 (d, J = 5.5 Hz, 1 H ), 7.94 (d, J = 9.4 Hz, 1 H), 7. 86 (dd, J = 9.1, 6.1 Hz, 1 H), 7.58-7.49 (m, 1 H), 7.37 (s, 1 H), 6.53 (d, J = 5.5 Hz, 1H), 3.66-3.32 (m, 2H), 2.54 (s, 2H), 2.09 (t, J = 7.7 Hz, 2H), 1.98-1.93 (m, 3H), 1.90-1.85 (m, 7H) ), 1.84-1.71 (m, 2H), 1.64 (t, J = 7.0 Hz, 2H), 1.59-1.55 (m, 5H), 1.02 (s, 3H)

Example 23
2- (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) -N-((1r, 3s, 5R, 7S) -3-hydroxyadamantan-1-yl) acetamide
To a mixture of 2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetic acid (22A, 26.5 mg, 0.09 mmol) in anhydrous DMF (1 mL) was added PyBOP ( 45.6 mg, 0.09 mmol) were added followed by DIPEA (0.06 mL, 0.3 mmol). The resulting mixture was stirred for 15 minutes, and (1s, 3r, 5R, 7S) -3-aminoadamantan-1-ol (17.6 mg, 0.1 mmol) was added. After stirring for 21 h at ambient temperature, the mixture was diluted with DMF, filtered through a syringe filter and purified by preparative HPLC / MS to give the title compound (13.4 mg; 27% yield). MS (ES): m / z = 452 [M + H] ⁺ .t _R = 1.18 min (Method B). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.35 (d, J = 5.4 Hz, 1 H ), 8.00-7. 92 (m, 1 H), 7. 86 (dd, J = 9.0, 6.1 Hz, 1 H), 7.57-7.49 (m, 1 H), 7.43 (s, 1 H), 6.53 (d, J = 5.4 Hz, 1H), 3.82-3.47 (m, 2H), 2.54 (s, 2H), 2.10-2.08 (m, 2H), 1.92-1.88 (m, 3H), 1.83-1.71 (m, 8H), 1.65 (t, J = 7.7 Hz, 2H), 1.53-1.36 (m, 6H), 1.02 (s, 3H)

Example 24
N-((3s, 5s, 7s) -adamantan-1-yl) -2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetamide
Acetyl chloride (1.1 mL, 15.2 mmol) was slowly added to a flask charged with methyl 2- (4-methylpiperidin-4-yl) acetate MeOH (7.5 mL) at 0 ° C. under a nitrogen atmosphere. . After the addition is complete, the mixture is stirred for 5 minutes at 0 ° C. to give a homogeneous mixture of 2- (4-methylpiperidin-4-yl) acetic acid, HCl (675.0 mg, 3.5 mmol) in MeOH (1.5 mL). It dripped slowly. The resulting homogeneous mixture is stirred at 0 ° C. for 5 minutes and then at 60 ° C. for 8 hours and concentrated under reduced pressure to give the HCl salt of the title compound as a white solid (718.0 mg; 99% yield), Was used without further purification. MS (ES): m / z = 172 [M + H] ⁺ .t _R = 0.46 min (Method A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.41-9.12 (m, 1 H), 3.60 (s, 3H), 3.25-3.15 (m, 2H), 2.93-2.82 (m, 2H), 2.39-2.30 (m, 2H), 1.74-1.64 (m, 4H), 1.02 (s, 3H)

24 B. Methyl 2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetate 4-chloro-2- (trifluoromethyl) pyridine (in a closed vial) A homogeneous mixture of 300.0 mg, 1.7 mmol) in anhydrous NMP (4 mL) is the HCl salt of methyl 2- (4-methylpiperidin-4-yl) acetate (24A, 412.0 mg, 2.0 mmol) followed by Then, DIPEA (1.3 mL, 7.4 mmol) was added. The vial was sealed and the mixture was stirred at 120 ° C. After 25 h, the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted once more with EtOAc. The organic layers were combined, washed with brine and concentrated under reduced pressure to give a crude product. Purification by Isco chromatography gave methyl 2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetate as an oil (461.1 mg; 88% yield). MS (ES): m / z = 317 [M + H] ⁺ .t _R = 0.65 min (Method A). ¹ H NMR (400 MHz, chloroform-d) δ 8.27 (d, J = 5.9 Hz, 1 H) , 6.70 (d, J = 2.4 Hz, 1 H), 6.43 (dd, J = 5.9, 2.4 Hz, 1 H), 3.69 (s, 3 H), 3.48-3.41 (m, 2H), 3.20-3.08 (m, 2H) ), 2.44-2.31 (m, 2H), 1.86-1.82 (m, 2H), 1.58 (s, 2H), 1.11 (s, 3H)

24C. 2- (4-Methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetic acid methyl 2- (4-methyl-1- (2- (trifluoromethyl)) To a homogenous mixture of pyridin-4-yl) piperidin-4-yl) acetate (461.1 mg, 1.5 mmol) in MeOH (5 mL) under a nitrogen atmosphere 2 M aqueous NaOH solution (1.6 mL, 3.2 mmol) It dripped. The reaction was stirred at ambient temperature for 13 hours and treated with 1 N HCl (aq) until pH 3-4 with pH paper. The mixture was partitioned between water and EtOAc, the layers separated, and the aqueous layer extracted twice with EtOAc. The organic layer from the extract was concentrated under reduced pressure to give the crude product HCl salt as a white solid (362.4 mg, 64% yield), which was used without further purification. MS (ES): m / z = 303 [M + H] ⁺ .t _R = 0.56 min (Method A). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (br. S, 1 H), 8.19 (d, J = 5.7 Hz, 1 H), 6.80 (d, J = 2.3 Hz, 1 H), 6. 63 (dd, J = 5.9, 2.3 Hz, 1 H), 3.43-3.37 (m, 2 H), 3.18-3.09 ( m, 2H), 2.35-2.23 (m, 2H), 1.87-1.72 (m, 2H), 1.71-1.63 (m, 2H), 1.02 (s, 3H)

Example 24. N-((3s, 5s, 7s) -adamantan-1-yl) -2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl A) Acetamido 2- (4-Methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetic acid HCl salt (24C, 25.6 mg, 0.09 mmol) in anhydrous DMF To a mixture in 1 mL) was added PyBOP (44.1 mg, 0.09 mmol) followed by DIPEA (0.06 mL, 0.3 mmol)). The resulting mixture was stirred for 15 minutes and (3s, 5s, 7s) -adamantan-1-amine (16.0 mg, 0.1 mmol) was added. After stirring for 15 h at ambient temperature, the mixture was diluted with DMF, filtered through a syringe filter and purified by preparative HPLC / MS to give the title compound (30.2 mg; 64% yield). MS (ES): m / z = 436 [M + H] ⁺ .t _R = 1.71 min (Method B). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.19 (d, J = 5.9 Hz, 1H ), 7.34 (s, 1H), 6.80 (s, 1H), 6.69-6.59 (m, 1H), 3.19-3.06 (m, 2H), 2.54 (s, 2H), 2.08 (t, J = 7.7 Hz, 2H), 2.01-1.94 (m, 3H), 1.92-1.87 (m, 6H), 1. 84-1.71 (m, 2H), 1.64-1.55 (m, 8H), 1.01 (s, 3H)

Materials and Methods In the following examples, the following general materials and methods can be used or used, if indicated.

  Standard methods of molecular biology are as described in the scientific literature (eg Sambrook et al., Molecular Cloning, Third Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001); and bacterial cells and DNA mutations Ausubel et al., Current describes cloning in induction (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3) and bioinformatics (Vol. 4). Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. (New York, NY (2001)).

  The scientific literature describes protein purification methods including immunoprecipitation, chromatography, electrophoresis, centrifugation and crystallization, and chemical analysis, chemical modification, post-translational modification, fusion protein production and protein glycosylation (eg Coligan et al., Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY (2000)).

  For example, software packages and databases for determining antigen fragments, leader sequences, protein folding, functional domains, glycosylation sites and sequence alignments are available (eg, GCG® Wisconsin Package (Accelrys, Inc., Inc., See San Diego, CA) and DECYPHER® (TimeLogic Corp., Crystal Bay, NV)).

  There is a wealth of literature on assays and other experimental techniques that can serve as a basis for the evaluation of the compounds described herein.

  IDO enzyme assay and cellular production of kynurenine (KYN) are described in Sarkar, S.A. et al., Diabetes, 56: 72-79 (2007). Briefly, all chemicals are purchased from Sigma-Aldrich (St. Louis, Mo.) unless otherwise stated. 1,000 human islets can be cultured with cytokines for 24 hours in 1 mL medium and recovered by centrifugation at 800 xg for 5 minutes and sonication in 150 μL PBS containing protease inhibitor cocktail (Set 2; Calbiochem, EMD Biosciences, San Diego, CA). The sonicate is centrifuged at 10,000 × g for 10 minutes, and the supernatant, 40 μl sample, 40 mmol / L ascorbic acid (neutralized to pH 7.0), 100 μmol / L methylene blue, 200 μg / mL catalase and Assays can be performed in triplicate by incubation for 30 minutes at 37 ° C. with an equal volume of 100 mmol / L potassium phosphate buffer, pH 6.5, containing 400 μmol / L L-Trp. The assay can be stopped by the addition of 16 μL 30% (w / v) trichloroacetic acid (TCA) and further incubated at 60 ° C. for 15 minutes to hydrolyze N-formylkynurenine into KYN. The mixture can then be incubated at 12,000 rpm for 15 minutes and KYN mixed with equal volumes of supernatant and 2% (w / v) Ehrlich's reagent in glacial acetic acid in a 96 well microtiter plate to prepare L-KYN It can be quantified by reading the absorbance at 480 nm. Protein in islet samples can be quantified by Bio-Rad protein assay at 595 nm. For L-KYN detection in islet culture supernatant, proteins can be precipitated with 5% (w / v) TCA, centrifuged at 12,000 rpm for 15 minutes, and determination of KYN using Ehrlich's reagent in the supernatant as described above. It can be determined as follows. IL-4 (10 μg / mL; 500-2,000 units / mL) and 1-α-methyl Trp (1-MT; 40 μmol / L) can be added to the incubation medium as described. This assay can also form the basis of a cell based assay, which can be quantified by LCMS / MS instead of UV / Vis detection.

Western blot analysis. The 1,000-1,200 islet groups incubated for 24 hours in Miami medium in the presence of cytokines can be recovered in PBS as described above, sonicated, and 50 μg protein samples can be electrophoresed on a 10% SDS-PAGE gel. Human-IDO plasmid (3 μg) or COS7 cells (0.6 × 10 ⁶ cells / 60 mm ³ petri dishes) transfected with empty vector cells can be used as positive and negative controls, respectively. The protein is transferred to a polyvinylidene fluoride membrane in a semi-dry method electrophoretically and blocked for 1 hour in Tris-buffered saline and 0.1% Tween with 5% (w / v) nonfat dry milk, anti-human mouse It can be incubated overnight with IDO antibody (1: 500; Chemicon, Temecula, CA), phospho-STAT _1α p91 and STAT _1α p91 (1: 500; Zymed, San Francisco, CA). Immunoreactive proteins can be visualized with ECL PLUS® Western Blotting Detection Reagent (Amersham BioSciences, Buckinghamshire, UK) after incubation with an anti-mouse horseradish peroxidase conjugated secondary antibody (Jackson Immunolabs, West Grove, PA) .

Immunohistochemical detection of IDO. Pancreatic islets are fixed in PBS with 4% paraformaldehyde (Invitrogen) for 1 hour, fixed in a 10% solution of porcine skin gelatin block (37 ° C.), and the compound embedded at optimal cutting temperature. Immunofluorescent staining of islet tissue can be performed on 7 μm sections stained with antibodies against pancreatic duodenal homeobox 1 (PDX1) and IDO. Antigen retrieval can be performed with a buffer containing 10 mmol / l Tris and 1 mmol / l EDTA (pH 9.0) for 30 minutes in a 97 ° C. water bath. Sections can be blocked with 5% normal goat serum in PBS for 1 hour. Tissues are mouse monoclonal anti-human IDO antibody (1:20; Chemicon) and goat polyclonal anti-human PDX1 antibody (1: 2,000; this is Dr. Chris Wright, School of Medicine, in a humidified chamber overnight at room temperature. Vanderbilt, which may be a request from TN). Secondary antibodies anti-goat (labeled with Cy3) and anti-mouse (labeled with Cy2) can be purchased from Jackson Immunolabs and used at a 1: 200 concentration. Nuclei can be stained with Hoechst 33258 (Molecular Probes, Eugene, OR). Images can be obtained with the Intelligent Imaging System system from an Olympus 1X81 inverted motorized microscope equipped with an Olympus DSU (turning board confocal) and a Hamamatsu ORCA IIER monochromatic CCD camera.

  Another means of evaluating the IDO inhibitors of the invention is described in WO 2010/0233166 and summarized below.

Biochemical assay. Both human and mouse IDO cDNA clones have been isolated, confirmed by sequencing, and are commercially available. To prepare IDO for biochemical studies, C-terminal His-tagged IDO protein can be produced in E. coli using the IPTG inducible pET5a vector system and isolated on a nickel column. The yield of partially purified protein is confirmed by gel electrophoresis, and the concentration can be estimated by comparison with a protein preparation. For IDO enzyme activity assays, 96-well plate spectrophotometric assays for kynurenine production can be performed by published methods (eg, Littlejohn, TK et al., Prot. Exp. Purif., 19: 22-29 ( 2000)). For IDO inhibitory activity screening, compounds are added at increasing concentrations of, for example, 0 μM, 2 μM, 20 μM and 200 μM, for example tryptophan at a single concentration of 200 μM to 50 ng of IDO enzyme in a 100 μL reaction volume Can be evaluated. Kynurenine production can be measured in one hour.

Cell based assay. COS-1 cells can be transiently transfected with a CMV promoter driven plasmid expressing IDO cDNA using Lipofectamine 2000 (Invitrogen) as recommended by the manufacturer. The cells of the companion set can be transiently transfected with TDO expression plasmids. After 48 hours of transfection, cells can be split at 6 × 10 ⁴ cells / well in a 98 well format. The next day, wells can be washed and fresh medium (phenol free red) containing 20 μg / mL tryptophan can be added along with the inhibitor. The reaction is stopped at 5 hours, the supernatant is removed and kynurenine can be assayed spectrophotometrically as described above for the enzyme assay. Compounds may be evaluated at a single concentration of, for example, 100 μM to obtain an initial confirmation of IDO activity. A broader dose escalation profile may be collected for selected compounds.

Pharmacodynamic and pharmacokinetic evaluation. Pharmacodynamic assays may be based on measurement of serum levels of both kynurenine and tryptophan, and calculation of kynurenine / tryptophan ratio provides an estimate of IDO activity independent of baseline tryptophan levels. Serum tryptophan and kynurenine levels can be determined by HPLC analysis, and serum compound levels can optionally be determined in the same HPLC run.

Compounds can be initially loaded with mice into LPS and subsequently assessed by administering bolus doses of compounds when serum kynurenine levels plateau. Pre-existing kynurenine is not predicted to over-mask the effect that IDO inhibitors have on kynurenine production, as kynurenine pools rapidly turnover with serum half-lives of less than 10 minutes. Each experiment included non-LPS exposed mice (to determine baseline kynurenine levels to compare other mice) and LPS exposed mice set administered vehicle alone (to provide a positive control for IDO activation) May be included. Each compound can be evaluated initially in mice at a single high ip bolus dose of at least 100 mg / kg. For HPLC analysis (pharmacodynamic analysis) of kynurenine and tryptophan levels and compound levels (pharmacokinetic analysis), defined time intervals (eg 50 μL sample for 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours of compound administration) Time, 4 hours, 6 hours, 8 hours and 24 hours) can be collected. From pharmacokinetic data, an approximate measure of the peak serum concentration achieved and the clearance of the compound can be determined. By comparing the kynurenine / tryptophan ratio at different time points with the compound level in serum, one can roughly estimate the effective IC ₅₀ of in vivo IDO inhibition. Compounds that show efficacy can be evaluated to determine the maximum weight to achieve 100% IDO inhibition at peak concentrations.

Evaluation of Biological Activity The exemplified compounds were tested for IDO activity inhibition. Experimental methods and results are provided below.

  HEK 293 cells were transfected by electroporation with a pcDNA based human IDO1 cDNA (NM 002164.2) carrying mammalian expression vector. The cells were cultured for 2 weeks in 1 mg / ml G418-containing medium (DMEM with 10% FBS). Clones of HEK293 cells stably expressing human IDO1 protein were selected and expanded for IDO inhibition assay.

Human IDO1 / HEK293 cells are seeded at a concentration of 100 nL in 10,000 cells / 50 μL / well with RPMI / phenol free medium containing 10% FBS in 384-well black wall clear bottom tissue culture plates (Matrix Technologies LLC) Compounds were added to each well using an ECHO liquid handling system. The cells were incubated with 5% CO ₂ for 20 hours in a 37 ° C. incubator.

  Compound treatment was stopped by adding trichloroacetic acid (Sigma-Aldrich) to a final concentration of 0.2%. The cell plate was further incubated at 50 ° C. for 30 minutes. Equal volumes of supernatant (20 μL) and 0.2% (w / v) Ehrlich's reagent (4-dimethylamino benzaldehyde, Sigma-Aldrich) in glacial acetic acid solution were mixed in a fresh clear bottom 384-well plate. The plate was incubated for 30 minutes at room temperature. Absorbance at 490 nm was measured on an Envision plate reader.

Compound IC ₅₀ values were calculated using a 500 nM count as the control treatment as 100% inhibition and a DMSO treatment count as the compound but as 0% inhibition.

Evaluation of inhibitor activity in HeLa cell based indoleamine 2,3-dioxygenase (IDO) assay.

HeLa (ATCC® CCL-2) cells are obtained from ATCC®, and are 4.5 g / L glucose, 4.5 g / L L-glutamine and 4.5 g / L sodium pyruvate (# 10- 013-CV, Corning), 2 mM L-alanyl-L-glutamine dipeptide (# 35050-061, Gibco), 100 U / mL penicillin, 100 μg / mL streptomycin (# SV 30010, HyClone) and 10% fetal bovine serum (# SH30071. 03 HyClone) supplemented with Dulbecco's modified Eagle's medium). The cells were maintained in 5% CO ₂ at 37 ° C. in a humidified incubator.

IDO activity was assessed as a function of kynurenine production as follows. HeLa cells were seeded at a density of 5,000 cells / well in 96 well culture plates and allowed to equilibrate overnight. After 24 hours, the medium was aspirated and replaced with medium containing IFNγ (# 285-IF / CF, R & D Systems) at a final concentration of 25 ng / mL. Serial dilutions of each test compound were added to the cells in a total volume of 200 μL culture medium. After an additional 48 hours of incubation, 170 μL of supernatant was transferred from each well to a fresh 96 well plate. 12.1 μL of 6.1 N trichloroacetic acid (# T0699, Sigma-Aldrich) is added to each well, mixed and subsequently incubated for 20 minutes at 65 ° C., the product of indoleamine 2,3-dioxygenase N-formylkynurenine was hydrolyzed to kynurenine. The reaction mixture was centrifuged at 500 × g for 10 minutes to precipitate the precipitate. 100 μL of supernatant was transferred from each well to a fresh 96 well plate. Add 100 μl of a solution of 2% (w / v) p-dimethylaminobenzaldehyde (# 15647-7, Sigma-Aldrich) in acetic acid (# A6283, Sigma-Aldrich) to each well, mix and incubate at room temperature for 20 minutes did. The kynurenine concentration is determined by measuring the absorbance at 480 nm and calibrating it against the L-kynurenine (# K8625, Sigma-Aldrich) standard curve using a SPECTRAMAX® M2e microplate reader (Molecular Devices) did. The percentage activity at each inhibitor concentration was determined and IC ₅₀ values were assessed using non-linear regression

The activity of the compounds described herein is provided below, where potency levels are indicated as follows. (Efficacy: IDO IC ₅₀ : A <0.1 μM; B <1 μM; C <10 μM).

The IDO assay results are shown in the table below.

Embodiments Embodiment 1. Formula I or Formula II
[In the formula,
X is CH or N;
T is CH or N;
R ¹ is H, halo or C ₁ -C ₆ haloalkyl;
R ^1A is H, halo or C ₁ -C ₆ haloalkyl;
Y is CH or N;
n is 0, 1, 2, 3 or 4;
W is N or CR ⁴ , wherein R ⁴ is H or (C ₁ -C ₆ alkyl);
V is _C 1 -C ₆ alkyl and _C 3 -C ₆ 1 or independently selected from cycloalkyl, in two or three may be substituted with a substituent _C 1 -C ₆ alkylene optionally ;
R ² is H or C ₁ -C ₆ alkyl;
Z is _C 1 -C ₆ alkyl and _C 3 -C ₆ 1 or independently selected from cycloalkyl, 2, or 3 substituents in optionally substituted _C 1 -C ₆ alkylene optionally ;
B is optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN, aryl or -O aryl independently Or aryl optionally substituted with one, two or three R substituents; or optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo,- OC ₁ -C ₆ alkyl, _-OC 1 -C ₆ haloalkyl, -CN, aryl or one independently selected from -O aryl, 2 or 3 may be substituted with R substituent _{C 3} -C is ₁₂ cycloalkyl].
Or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof.
Aspect 2. A compound of aspect 1 which is a compound of formula I.
Aspect 3. The compound of aspect 1, which is a compound of formula II.
Aspect 4. The compound of any of the preceding aspects, wherein R ¹ is H, F or —CF ₃ .
Aspect 5. The compound of any of the preceding aspects, wherein R ^1A is H.
Aspect 6. The compound of any of the above aspects wherein Y is CH.
Aspect 7. The compound according to any of the aspects 1 to 3, wherein Y is N.
Embodiment 8 A compound according to any of the embodiments above wherein n is 2.
Aspects 9. W is CR ^4, any of the compounds of the embodiments.
Aspect 10. The compound according to any of the aspects 1 to 8, wherein W is N.
Embodiment 11. V is _C 1 -C ₆ alkyl or _C 3 -C ₆ cycloalkyl in which 1 which may have _{C 1} alkylene substituted with a substituent optionally has any of the compounds of the embodiments.
Aspect 12. The above aspect, wherein Z is C ₁ alkylene optionally substituted with one or two substituents independently selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl. Any compound of
Embodiment 13. -OH optionally B _is, C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, halo, _-OC 1 -C ₆ alkyl, _-OC 1 -C ₆ haloalkyl, -CN, aryl, or -O aryl 13. The compound of any of claims 1-12, which is aryl optionally substituted with one, two or three R substituents independently selected from
Embodiment 14. -OH optionally B _is, C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, halo, _-OC 1 -C ₆ alkyl, _-OC 1 -C ₆ haloalkyl, -CN, aryl, or -O aryl 14. The compound of aspect 13, which is phenyl optionally substituted with one or two R substituents independently selected from
Embodiment 15. -OH optionally B _is, C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, halo, _-OC 1 -C ₆ alkyl, _-OC 1 -C ₆ haloalkyl, -CN, aryl, or -O aryl 1 substituents independently selected from 2 or 3 is to be C ₃ -C ₁₂ optionally cycloalkyl substituted with R substituent, any of the compounds of aspects 1-12.
Embodiment 16. The following N- (4-chloro-2-methylbenzyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
N- (1- (2,4-Dichlorophenyl) cyclo-propyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
-(2- (4-chlorophenyl) propan-2-yl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
(S) -N- (1- (4-chlorophenyl) ethyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
N- (4-Chlorobenzyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
(S) -2- (4-Methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) -N- (1-phenylpropyl) acetamide;
N- (1- (2,4-Dichlorophenyl) cyclo-propyl) -2- (4-methyl-1- (2- (trifluoro-methyl) pyridin-4-yl) piperidin-4-yl) acetamide;
N- (2- (4-Chlorophenyl) propan-2-yl) -2- (4-methyl-1- (2- (trifluoromethyl) -pyridin-4-yl) piperidin-4-yl) acetamide;
(S) -N- (1- (4-chlorophenyl) ethyl) -2- (4-methyl-1- (2- (trifluoromethyl) -pyridin-4-yl) piperidin-4-yl) acetamide;
(R) -N- (2-chlorobenzyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N- (2-chlorobenzyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-([1,1′-biphenyl] -4-ylmethyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) -N-((S) -1-phenylethyl) propanamide;
(R) -N-((S) -1- (4-chlorophenyl) ethyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-((S) -1- (4-chlorophenyl) ethyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N- (1- (2,4-dichlorophenyl) cyclopropyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-((R) -1- (4-chlorophenyl) ethyl) -2-((1s, 4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-benzyl-2-((1s, 4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide;
N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide;
(cis)-(2R) -N- (3,5-dimethyladamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
N-((3s, 5s, 7s) -adamantan-1-yl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
2- (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) -N-((1r, 3s, 5R, 7S) -3-hydroxyadamantan-1-yl) acetamide; Or N-((3s, 5s, 7s) -adamantan-1-yl) -2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetamide;
Or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof.
Aspect 17. A pharmaceutical composition comprising a compound of any of aspects 1 to 16 and a pharmaceutically acceptable carrier.
Embodiment 18 The pharmaceutical composition of Embodiment 17, further comprising Javoy, Opsibo or Keytoruda, or a combination thereof.
Aspect 19. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any of aspects 1-16.

Claims (19)

Formula I or Formula II
[In the formula,
X is CH or N;
T is CH or N;
R ¹ is H, halo or C ₁ -C ₆ haloalkyl;
R ^1A is H, halo or C ₁ -C ₆ haloalkyl;
Y is CH or N;
n is 0, 1, 2, 3 or 4;
W is N or CR ⁴ , wherein R ⁴ is H or (C ₁ -C ₆ alkyl);
V is _C 1 -C ₆ alkyl and _C 3 -C ₆ 1 or independently selected from cycloalkyl, in two or three may be substituted with a substituent _C 1 -C ₆ alkylene optionally ;
R ² is H or C ₁ -C ₆ alkyl;
Z is one independently selected from the group consisting of C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl by binding or case, two or three may be substituted with a substituent C ₁ - C ₆ alkylene;
B is optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN, aryl or -O aryl independently Or aryl optionally substituted with one, two or three R substituents; or optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo,- OC ₁ -C ₆ alkyl, _-OC 1 -C ₆ haloalkyl, -CN, aryl or one independently selected from -O aryl, 2 or 3 may be substituted with R substituent _{C 3} -C is ₁₂ cycloalkyl. ]
Or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof.   A compound according to claim 1 which is a compound of formula I.   A compound according to claim 1 which is a compound of formula II. R ¹ is H, F or -CF _3, A compound according to any one of claims 1 to 3. ^5. A compound according to any of the preceding claims, wherein ^R1A is H.   A compound according to any of claims 1 to 5, wherein Y is CH.   A compound according to any of claims 1 to 3 wherein Y is N.   A compound according to any of claims 1 to 7, wherein n is 2. W is CR ^4, A compound according to any one of claims 1 to 8.   9. A compound according to any of the preceding claims, wherein W is N. V is _C 1 -C ₆ alkyl or _C 3 -C ₆ cycloalkyl in which 1 which may have _{C 1} alkylene substituted with a substituent optionally, a compound according to any one of claims 1 to 10. 12. Z is optionally substituted C ₁ alkylene optionally substituted with one or two substituents independently selected from C ₁ -C ₆ alkyl and C ₃ -C ₆ cycloalkyl. The compound as described in any of the above. B is optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN, aryl or -O aryl independently The compound according to any one of claims 1 to 12, which is an aryl optionally substituted with one, two or three R substituents selected. B is optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN, aryl or -O aryl independently 14. The compound according to claim 13, which is phenyl optionally substituted by one or two R substituents selected. B is optionally -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halo, -OC ₁ -C ₆ alkyl, -OC ₁ -C ₆ haloalkyl, -CN, aryl or -O aryl independently one selected Te, two or three R substituents may C ₃ -C ₁₂ cycloalkyl optionally substituted by a group a compound according to any one of claims 1 to 12. The following N- (4-chloro-2-methylbenzyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
N- (1- (2,4-Dichlorophenyl) cyclo-propyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
-(2- (4-chlorophenyl) propan-2-yl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
(S) -N- (1- (4-chlorophenyl) ethyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
N- (4-Chlorobenzyl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
(S) -2- (4-Methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) -N- (1-phenylpropyl) acetamide;
N- (1- (2,4-Dichlorophenyl) cyclo-propyl) -2- (4-methyl-1- (2- (trifluoro-methyl) pyridin-4-yl) piperidin-4-yl) acetamide;
N- (2- (4-Chlorophenyl) propan-2-yl) -2- (4-methyl-1- (2- (trifluoromethyl) -pyridin-4-yl) piperidin-4-yl) acetamide;
(S) -N- (1- (4-chlorophenyl) ethyl) -2- (4-methyl-1- (2- (trifluoromethyl) -pyridin-4-yl) piperidin-4-yl) acetamide;
(R) -N- (2-chlorobenzyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N- (2-chlorobenzyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-([1,1′-biphenyl] -4-ylmethyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) -N-((S) -1-phenylethyl) propanamide;
(R) -N-((S) -1- (4-chlorophenyl) ethyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-((S) -1- (4-chlorophenyl) ethyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N- (1- (2,4-dichlorophenyl) cyclopropyl) -2-((cis) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-((R) -1- (4-chlorophenyl) ethyl) -2-((1s, 4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
(R) -N-benzyl-2-((1s, 4S) -4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
N-((3R, 5R, 7R) -adamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) piperazin-1-yl) pentanamide;
N- (adamantan-2-yl) -2- (1-((6- (trifluoromethyl) pyridin-2-yl) methyl) piperidin-4-yl) butanamide;
(cis)-(2R) -N- (3,5-dimethyladamantan-1-yl) -2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) propanamide;
N-((3s, 5s, 7s) -adamantan-1-yl) -2- (1- (6-fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) acetamide;
2- (1- (6-Fluoroquinolin-4-yl) -4-methylpiperidin-4-yl) -N-((1r, 3s, 5R, 7S) -3-hydroxyadamantan-1-yl) acetamide; Or N-((3s, 5s, 7s) -adamantan-1-yl) -2- (4-methyl-1- (2- (trifluoromethyl) pyridin-4-yl) piperidin-4-yl) acetamide;
The compound according to claim 1, which is a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof or a solvate thereof.   A pharmaceutical composition comprising a compound according to any of claims 1-16 and a pharmaceutically acceptable carrier.   18. The pharmaceutical composition according to claim 17, further comprising Yavoy, Opsibo or Keytoruda or a combination thereof.   22. A method of treating cancer in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a compound according to any of claims 1-16.